Journal articles: 'Soluble tau protein'

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Webster, Jack M., April L. Darling, Taylor A. Sanders, Danielle M. Blazier, Yamile Vidal-Aguiar, David Beaulieu-Abdelahad, Drew G. Plemmons, et al. "Hsp22 with an N-Terminal Domain Truncation Mediates a Reduction in Tau Protein Levels." International Journal of Molecular Sciences 21, no. 15 (July 30, 2020): 5442. http://dx.doi.org/10.3390/ijms21155442.

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Misfolding, aggregation and accumulation of proteins are toxic elements in the progression of a broad range of neurodegenerative diseases. Molecular chaperones enable a cellular defense by reducing or compartmentalizing these insults. Small heat shock proteins (sHsps) engage proteins early in the process of misfolding and can facilitate their proper folding or refolding, sequestration, or clearance. Here, we evaluate the effects of the sHsp Hsp22, as well as a pseudophosphorylated mutant and an N-terminal domain deletion (NTDΔ) variant on tau aggregation in vitro and tau accumulation and aggregation in cultured cells. Hsp22 wild-type (WT) protein had a significant inhibitory effect on heparin-induced aggregation in vitro and the pseudophosphorylated mutant Hsp22 demonstrated a similar effect. When co-expressed in a cell culture model with tau, these Hsp22 constructs significantly reduced soluble tau protein levels when transfected at a high ratio relative to tau. However, the Hsp22 NTDΔ protein drastically reduced the soluble protein expression levels of both tau WT and tau P301L/S320F even at lower transfection ratios, which resulted in a correlative reduction of the triton-insoluble tau P301L/S320F aggregates.

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Rank, Kenneth B., Adele M. Pauley, Keshab Bhattacharya, Zhigang Wang, David B. Evans, Timothy J. Fleck, Jennifer A. Johnston, and Satish K. Sharma. "Direct interaction of soluble human recombinant tau protein with Aβ 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II." FEBS Letters 514, no. 2-3 (March 13, 2002): 263–68. http://dx.doi.org/10.1016/s0014-5793(02)02376-1.

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Zhao, Yanyan, Ole Tietz, Wei-Li Kuan, Abdul K. Haji-Dheere, Stephen Thompson, Benjamin Vallin, Elisabetta Ronchi, Gergely Tóth, David Klenerman, and Franklin I. Aigbirhio. "A fluorescent molecular imaging probe with selectivity for soluble tau aggregated protein." Chemical Science 11, no. 18 (2020): 4773–78. http://dx.doi.org/10.1039/c9sc05620c.

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Chatterjee, Shreyasi, Megan Sealey, Eva Ruiz, Chrysia M. Pegasiou, Keeley Brookes, Sam Green, Anna Crisford, et al. "Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration." PLOS ONE 18, no. 1 (January 26, 2023): e0262792. http://dx.doi.org/10.1371/journal.pone.0262792.

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Tau becomes abnormally hyper-phosphorylated and aggregated in tauopathies like Alzheimers disease (AD). As age is the greatest risk factor for developing AD, it is important to understand how tau protein itself, and the pathways implicated in its turnover, change during aging. We investigated age-related changes in total and phosphorylated tau in brain samples from two cohorts of cognitively normal individuals spanning 19–74 years, without overt neurodegeneration. One cohort utilised resected tissue and the other used post-mortem tissue. Total soluble tau levels declined with age in both cohorts. Phosphorylated tau was undetectable in the post-mortem tissue but was clearly evident in the resected tissue and did not undergo significant age-related change. To ascertain if the decline in soluble tau was correlated with age-related changes in autophagy, three markers of autophagy were tested but only two appeared to increase with age and the third was unchanged. This implies that in individuals who do not develop neurodegeneration, there is an age-related reduction in soluble tau which could potentially be due to age-related changes in autophagy. Thus, to explore how an age-related increase in autophagy might influence tau-mediated dysfunctions in vivo, autophagy was enhanced in a Drosophila model and all age-related tau phenotypes were significantly ameliorated. These data shed light on age-related physiological changes in proteins implicated in AD and highlights the need to study pathways that may be responsible for these changes. It also demonstrates the therapeutic potential of interventions that upregulate turnover of aggregate-prone proteins during aging.

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Mroczko, Groblewska, and Litman-Zawadzka. "The Role of Protein Misfolding and Tau Oligomers (TauOs) in Alzheimer′s Disease (AD)." International Journal of Molecular Sciences 20, no. 19 (September 20, 2019): 4661. http://dx.doi.org/10.3390/ijms20194661.

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Although the causative role of the accumulation of amyloid β 1–42 (Aβ42) deposits in the pathogenesis of Alzheimer′s disease (AD) has been under debate for many years, it is supposed that the toxicity soluble oligomers of Tau protein (TauOs) might be also the pathogenic factor acting on the initial stages of this disease. Therefore, we performed a thorough search for literature pertaining to our investigation via the MEDLINE/PubMed database. It was shown that soluble TauOs, especially granular forms, may be the most toxic form of this protein. Hyperphosphorylated TauOs can reduce the number of synapses by missorting into axonal compartments of neurons other than axon. Furthermore, soluble TauOs may be also responsible for seeding Tau pathology within AD brains, with probable link to AβOs toxicity. Additionally, the concentrations of TauOs in the cerebrospinal fluid (CSF) and plasma of AD patients were higher than in non-demented controls, and revealed a negative correlation with mini-mental state examination (MMSE) scores. It was postulated that adding the measurements of TauOs to the panel of CSF biomarkers could improve the diagnosis of AD.

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Gyparaki, Melina Theoni, Arian Arab, Elena M. Sorokina, Adriana N. Santiago-Ruiz, Christopher H. Bohrer, Jie Xiao, and Melike Lakadamyali. "Tau forms oligomeric complexes on microtubules that are distinct from tau aggregates." Proceedings of the National Academy of Sciences 118, no. 19 (May 5, 2021): e2021461118. http://dx.doi.org/10.1073/pnas.2021461118.

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Tau is a microtubule-associated protein, which promotes neuronal microtubule assembly and stability. Accumulation of tau into insoluble aggregates known as neurofibrillary tangles (NFTs) is a pathological hallmark of several neurodegenerative diseases. The current hypothesis is that small, soluble oligomeric tau species preceding NFT formation cause toxicity. However, thus far, visualizing the spatial distribution of tau monomers and oligomers inside cells under physiological or pathological conditions has not been possible. Here, using single-molecule localization microscopy, we show that tau forms small oligomers on microtubules ex vivo. These oligomers are distinct from those found in cells exhibiting tau aggregation and could be precursors of aggregated tau in pathology. Furthermore, using an unsupervised shape classification algorithm that we developed, we show that different tau phosphorylation states are associated with distinct tau aggregate species. Our work elucidates tau’s nanoscale composition under nonaggregated and aggregated conditions ex vivo.

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Cowan, Catherine M., Shmma Quraishe, and Amritpal Mudher. "What is the pathological significance of tau oligomers?" Biochemical Society Transactions 40, no. 4 (July 20, 2012): 693–97. http://dx.doi.org/10.1042/bst20120135.

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Insoluble aggregates of the microtubule-associated protein tau characterize a number of neurodegenerative diseases collectively termed tauopathies. These aggregates comprise abnormally hyperphosphorylated and misfolded tau proteins. Research in this field has traditionally focused on understanding how hyperphosphorylated and aggregated tau mediates dysfunction and toxicity in tauopathies. Recent findings from both Drosophila and rodent models of tauopathy suggest that large insoluble aggregates such as tau filaments and tangles may not be the key toxic species in these diseases. Thus some investigators have shifted their focus to study pre-filament tau species such as tau oligomers and hyperphosphorylated tau monomers. Interestingly, tau oligomers can exist in a variety of states including hyperphosphorylated and unphosphorylated forms, which can be both soluble and insoluble. It remains to be determined which of these oligomeric states of tau are causally involved in neurodegeneration and which signal the beginning of the formation of inert/protective filaments. It will be important to better understand this so that tau-based therapeutic interventions can target the most toxic tau species.

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Yu, Hai-Yang, Dong-Mei Gao, Wei Zhou, Bing-Bing Xia, Zhi-Yuan He, Bo Wu, Min-Zhi Jiang, Ming-Li Wang, and Jun Zhao. "Expression, purification, and bioactivity of a soluble recombinant ovine interferon-tau in Escherichia coli." Journal of Veterinary Research 65, no. 1 (January 29, 2021): 101–8. http://dx.doi.org/10.2478/jvetres-2021-0011.

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Abstract Introduction Ovine interferon-tau (oIFN-τ) is a newly discovered type I interferon. This study used biochemical techniques to transform the oIFN-τ gene into Escherichia coli to obtain the mass and soluble expression of the recombinant protein. Material and Methods First, total RNA was extracted from fresh sheep embryonic tissues with TRIzol reagent and then used as a template to reverse transcribe and amplify the mature oIFN-τ gene with RT-PCR. The amplified product was next digested with the HindIII and XhoI restriction enzymes and inserted into the pET-32a(+) vector to construct the prokaryotic expression plasmid. The corrected in-frame recombinant plasmid, pET-32a(+)-oIFN-τ, was transformed into E. coli Rosetta (DE3) competent cells. After induction with isopropyl-beta-D-thiogalactopyranoside (IPTG), the recombinant protein was detected in bacteria. Finally, the bacteria were lysed by sonication, and the recombinant protein was purified by nickel affinity chromatography and DEAE anion exchange chromatography. Results The protein was confirmed to be oIFN-τ, which mainly existed in the soluble lysate fraction, as proven by SDS-PAGE and Western blot assays. Conclusion Purified IFN-τ exists mostly in a soluble form, and its anti-vesicular stomatitis virus (VSV) activity reached 7.08×10(6)IU/mL.

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Lin, Gaoping, Feiyan Zhu, Nicholas M. Kanaan, Rei Asano, Norimichi Shirafuji, Hirohito Sasaki, Tomohisa Yamaguchi, et al. "Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein." International Journal of Molecular Sciences 22, no. 21 (November 8, 2021): 12063. http://dx.doi.org/10.3390/ijms222112063.

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The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 μM CQ had no effect on cell viability; however, 100 μM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.

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Vitali, Antonella, Alessandra Piccini, Roberta Borghi, Pantaleo Fornaro, Sandra L. Siedlak, Mark A. Smith, Pierluigi Gambetti, Bernardino Ghetti, and Massimo Tabaton. "Soluble amyloid β-protein is increased in frontotemporal dementia with tau gene mutations." Journal of Alzheimer's Disease 6, no. 1 (February 20, 2004): 45–51. http://dx.doi.org/10.3233/jad-2004-6106.

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Corbett, Grant T., Zemin Wang, Wei Hong, Marti Colom-Cadena, Jamie Rose, Meichen Liao, Adhana Asfaw, et al. "PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins." Acta Neuropathologica 139, no. 3 (December 18, 2019): 503–26. http://dx.doi.org/10.1007/s00401-019-02114-9.

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AbstractNeurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of α-synuclein and tau bind to plate-immobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble Aβ aggregates bind. Moreover, soluble aggregates of tau, α-synuclein and Aβ cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking PRNP, and (2) aqueous extracts from brains of individuals who died with Alzheimer’s disease, dementia with Lewy bodies, and Pick’s disease, we demonstrate that Aβ, α-synuclein and tau are toxic to neurons in a manner that requires PrPC. These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.

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Zhu, Yuanhui, Xi Wang, Miaoyang Hu, Tingyu Yang, Huaisha Xu, Xiuwen Kang, Xufeng Chen, Lei Jiang, Rong Gao, and Jun Wang. "Targeting Aβ and p-Tau Clearance in Methamphetamine-Induced Alzheimer’s Disease-Like Pathology: Roles of Syntaxin 17 in Autophagic Degradation in Primary Hippocampal Neurons." Oxidative Medicine and Cellular Longevity 2022 (May 18, 2022): 1–18. http://dx.doi.org/10.1155/2022/3344569.

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Methamphetamine (Meth), a central nervous system (CNS) stimulant with strong neurotoxicity, causes progressive cognitive impairment with characterized neurodegenerative changes. However, the mechanism underlying Meth-induced pathological changes remains poorly understood. In the current study, Meth elicited a striking accumulation of the pathological proteins hyperphosphorylated tau (p-tau) and amyloid beta (Aβ) in primary hippocampal neurons, while the activation of autophagy dramatically ameliorated the high levels of these pathological proteins. Interestingly, after the Meth treatment, Aβ was massively deposited in autophagosomes, which were remarkably trapped in early endosomes. Mechanistically, syntaxin 17 (Stx17), a key soluble n-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor (SNARE) protein responsible for autophagosome and mature endosome/lysosome fusion, was significantly downregulated and hindered in combination with autophagosomes. Notably, adenovirus overexpression of Stx17 in primary neurons facilitated autophagosome-mature endosome/lysosome fusion, which dramatically reversed the Meth-induced increases in the levels of p-tau, Aβ, beta-secretase (Bace-1), and C-terminal fragments (CTFs). Immunofluorescence assays showed that Stx17 retarded the Meth-induced Aβ, p-tau, and Bace-1 accumulation in autophagosomes and facilitated the translocation of these pathological proteins to lysosomes, which indicated the importance of Stx17 via enhanced autophagosome-mature endosome/lysosome fusion. Therefore, the current study reveals a novel mechanism involving Meth-induced high levels of pathological proteins in neurons. Targeting Stx17 may provide a novel therapeutic strategy for Meth-induced neurodegenerative changes.

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JENKINS, Scott M., Marcus ZINNERMAN, Craig GARNER, and Gail V. W. JOHNSON. "Modulation of tau phosphorylation and intracellular localization by cellular stress." Biochemical Journal 345, no. 2 (January 10, 2000): 263–70. http://dx.doi.org/10.1042/bj3450263.

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Tau is a microtubule-associated protein that is functionally modulated by phosphorylation and hyperphosphorylated in several neurodegenerative diseases. Because phosphorylation regulates both normal and pathological tau functioning, it is of great interest to identify the signalling pathways and enzymes capable of modulating tau phosphorylation in vivo. The present study examined changes in tau phosphorylation and localization in response to osmotic stress, which activates the stress-activated protein kinases (SAPKs), a family of proline-directed protein kinases shown to phosphorylate tau in vitro and hypothesized to phosphorylate tau in Alzheimer's disease. Immunoblot analysis with phosphorylation-dependent antibodies revealed that osmotic stress increased tau phosphorylation at the non-Ser/Thr-Pro sites Ser-262/356, within the microtubule-binding domain, as well as Ser/Thr-Pro sites outside of tau's microtubule-binding domain. Although all SAPKs examined were activated by osmotic stress, none of the endogenous SAPKs mediated the increase in tau phosphorylation. However, when transfected into SH-SY5Y cells, SAPK3, but not the other SAPKs examined, phosphorylated tau in situ in response to activation by osmotic stress. Osmotic-stress-induced tau phosphorylation correlated with a decrease in the amount of tau associated with the cytoskeleton and an increase in the amount of soluble tau. This stress-induced alteration in tau localization was only partially due to phosphorylation at Ser-262/356 by a staurosporine-sensitive, non-proline-directed, protein kinase. Taken together, these results suggest that osmotic stress activates at least two tau-directed protein kinases, one proline-directed and one non-proline-directed, that SAPK3 can phosphorylate tau on Ser/Thr-Pro residues in situ, and that Ser-262/356 phosphorylation only partially regulates tau localization in the cell.

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Penke, Botond, Ferenc Bogár, Gábor Paragi, János Gera, and Lívia Fülöp. "Key Peptides and Proteins in Alzheimer’s Disease." Current Protein & Peptide Science 20, no. 6 (May 20, 2019): 577–99. http://dx.doi.org/10.2174/1389203720666190103123434.

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Alzheimer’s Disease (AD) is a form of progressive dementia involving cognitive impairment, loss of learning and memory. Different proteins (such as amyloid precursor protein (APP), β- amyloid (Aβ) and tau protein) play a key role in the initiation and progression of AD. We review the role of the most important proteins and peptides in AD pathogenesis. The structure, biosynthesis and physiological role of APP are shortly summarized. The details of trafficking and processing of APP to Aβ, the cytosolic intracellular Aβ domain (AICD) and small soluble proteins are shown, together with other amyloid-forming proteins such as tau and α-synuclein (α-syn). Hypothetic physiological functions of Aβ are summarized. The mechanism of conformational change, the formation and the role of neurotoxic amyloid oligomeric (oAβ) are shown. The fibril formation process and the co-existence of different steric structures (U-shaped and S-shaped) of Aβ monomers in mature fibrils are demonstrated. We summarize the known pathogenic and non-pathogenic mutations and show the toxic interactions of Aβ species after binding to cellular receptors. Tau phosphorylation, fibrillation, the molecular structure of tau filaments and their toxic effect on microtubules are shown. Development of Aβ and tau imaging in AD brain and CSF as well as blood biomarkers is shortly summarized. The most probable pathomechanisms of AD including the toxic effects of oAβ and tau; the three (biochemical, cellular and clinical) phases of AD are shown. Finally, the last section summarizes the present state of Aβ- and tau-directed therapies and future directions of AD research and drug development.

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Lo, Chih Hung. "Heterogeneous Tau Oligomers as Molecular Targets for Alzheimer’s Disease and Related Tauopathies." Biophysica 2, no. 4 (November 11, 2022): 440–51. http://dx.doi.org/10.3390/biophysica2040039.

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Tauopathies, including Alzheimer’s disease (AD), are a group of neurodegenerative disorders characterized by pathological aggregation of microtubule binding protein tau. The presence of tau neurofibrillary tangles, which are insoluble β-sheet fibrils, in the brain has been the histopathological hallmark of these diseases as their level correlates with the degree of cognitive impairment. However, recent studies suggest that tau oligomers, which are soluble proteins that are formed prior to insoluble fibrils, are the principal toxic species impairing neurons and inducing neurodegeneration. Targeting toxic tau oligomers is challenging, as they are mostly unstructured and adopting multiple conformations. The heterogeneity of tau oligomers is further illustrated by the different oligomeric species formed by various methods. The current models and technologies to study tau oligomerization represent important resources and avenues to push the forefront of elucidating the true toxic tau species. In this review, we will summarize the distinct tau oligomers generated using different strategies and discuss their conformational characteristics, neurotoxicity, relevance to pathological phenotypes, as well as their applications in drug discovery. This information will provide insights to understanding heterogeneous tau oligomers and their role as molecular targets for AD and related tauopathies.

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Sontag, Jean-Marie, Viyada Nunbhakdi-Craig, and Estelle Sontag. "Leucine Carboxyl Methyltransferase 1 (LCMT1)-dependent Methylation Regulates the Association of Protein Phosphatase 2A and Tau Protein with Plasma Membrane Microdomains in Neuroblastoma Cells." Journal of Biological Chemistry 288, no. 38 (August 13, 2013): 27396–405. http://dx.doi.org/10.1074/jbc.m113.490102.

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Down-regulation of protein phosphatase 2A (PP2A) methylation occurs in Alzheimer disease (AD). However, the regulation of PP2A methylation remains poorly understood. We have reported that altered leucine carboxyl methyltransferase (LCMT1)-dependent PP2A methylation is associated with down-regulation of PP2A holoenzymes containing the Bα subunit (PP2A/Bα) and subsequent accumulation of phosphorylated Tau in N2a cells, in vivo and in AD. Here, we show that pools of LCMT1, methylated PP2A, and PP2A/Bα are co-enriched in cholesterol-rich plasma membrane microdomains/rafts purified from N2a cells. In contrast, demethylated PP2A is preferentially distributed in non-rafts wherein small amounts of the PP2A methylesterase PME-1 are exclusively present. A methylation-incompetent PP2A mutant is excluded from rafts. Enhanced methylation of PP2A promotes the association of PP2A and Tau with the plasma membrane. Altered PP2A methylation following expression of a catalytically inactive LCMT1 mutant, knockdown of LCMT1, or alterations in one-carbon metabolism all result in a loss of plasma membrane-associated PP2A and Tau in N2a cells. This correlates with accumulation of soluble phosphorylated Tau, a hallmark of AD and other tauopathies. Thus, our findings reveal a distinct compartmentalization of PP2A and PP2A regulatory enzymes in plasma membrane microdomains and identify a novel methylation-dependent mechanism involved in modulating the targeting of PP2A, and its substrate Tau, to the plasma membrane. We propose that alterations in the membrane localization of PP2A and Tau following down-regulation of LCMT1 may lead to PP2A and Tau dysfunction in AD.

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Deng, Juan, Ahsan Habib, Demian F. Obregon, Steven W. Barger, Brian Giunta, Yan-Jiang Wang, Huayan Hou, Darrell Sawmiller, and Jun Tan. "Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3β signaling pathway." Journal of Neurochemistry 135, no. 3 (September 24, 2015): 630–37. http://dx.doi.org/10.1111/jnc.13351.

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O'Neill, Cora, Aoife P. Kiely, Meghan F. Coakley, Sean Manning, and Caitriona M. Long-Smith. "Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease." Biochemical Society Transactions 40, no. 4 (July 20, 2012): 721–27. http://dx.doi.org/10.1042/bst20120080.

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The quality control of protein homoeostasis deteriorates with aging, causing the accumulation of misfolded proteins and neurodegeneration. Thus, in AD (Alzheimer's disease), soluble oligomers, protofibrils and fibrils of the Aβ (amyloid β-peptide) and tau protein accumulate in specific brain regions. This is associated with the progressive destruction of synaptic circuits controlling memory and higher mental function. The primary signalling mechanisms that (i) become defective in AD to alter the normal proteostasis of Aβ and tau, and (ii) initiate a pathophysiological response to cause cognitive decline, are unclear. The IIS [insulin/IGF-1 (insulin-like growth factor 1)-like signalling] pathway is mechanistically linked to longevity, protein homoeostasis, learning and memory, and is emerging to be central to both (i) and (ii). This pathway is aberrantly overactivated in AD brain at the level of increased activation of the serine/threonine kinase Akt and the phosphorylation of its downstream targets, including mTOR (mammalian target of rapamycin). Feedback inhibition of normal insulin/IGF activation of the pathway also occurs in AD due to inactivation of IRS-1 (insulin receptor substrate 1) and decreased IRS-1/2 levels. Pathogenic forms of Aβ may induce aberrant sustained activation of the PI3K (phosphoinositide 3-kinase)/Akt signal in AD, also causing non-responsive insulin and IGF-1 receptor, and altered tau phosphorylation, conformation and function. Reducing IIS activity in animal models by decreasing IGF-1R levels or inhibiting mTOR activity alters Aβ and tau protein homoeostasis towards less toxic protein conformations, improves cognitive function and extends healthy lifespan. Thus normalizing IIS dysfunction may be therapeutically relevant in abrogating Aβ and tau proteotoxicity, synaptic dysfunction and cognitive decline in AD.

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Jeppsson, Anna, Carsten Wikkelsö, Kaj Blennow, Henrik Zetterberg, Radu Constantinescu, Anne M. Remes, Sanna-Kaisa Herukka, et al. "CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics." Journal of Neurology, Neurosurgery & Psychiatry 90, no. 10 (June 5, 2019): 1117–23. http://dx.doi.org/10.1136/jnnp-2019-320826.

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ObjectiveTo examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer’s disease-related amyloid β (Aβ) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders.MethodsThe study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson’s disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer’s disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1).ResultsPatients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers.ConclusionsThe combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.

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Song, Liqing, Evan A. Wells, and Anne Skaja Robinson. "Critical Molecular and Cellular Contributors to Tau Pathology." Biomedicines 9, no. 2 (February 14, 2021): 190. http://dx.doi.org/10.3390/biomedicines9020190.

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Tauopathies represent a group of neurodegenerative diseases including Alzheimer’s disease (AD) that are characterized by the deposition of filamentous tau aggregates in the brain. The pathogenesis of tauopathies starts from the formation of toxic ‘tau seeds’ from hyperphosphorylated tau monomers. The presence of specific phosphorylation sites and heat shock protein 90 facilitates soluble tau protein aggregation. Transcellular propagation of pathogenic tau into synaptically connected neuronal cells or adjacent glial cells via receptor-mediated endocytosis facilitate disease spread through the brain. While neuroprotective effects of glial cells—including phagocytotic microglial and astroglial phenotypes—have been observed at the early stage of neurodegeneration, dysfunctional neuronal-glial cellular communication results in a series of further pathological consequences as the disease progresses, including abnormal axonal transport, synaptic degeneration, and neuronal loss, accompanied by a pro-inflammatory microenvironment. Additionally, the discovery of microtubule-associated protein tau (MAPT) gene mutations and the strongest genetic risk factor of tauopathies—an increase in the presence of the ε2 allele of apolipoprotein E (ApoE)—provide important clues to understanding tau pathology progression. In this review, we describe the crucial signaling pathways and diverse cellular contributors to the progression of tauopathies. A systematic understanding of disease pathogenesis provides novel insights into therapeutic targets within altered signaling pathways and is of great significance for discovering effective treatments for tauopathies.

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Hanger, D. P., J. P. Brion, J. M. Gallo, N. J. Cairns, P. J. Luthert, and B. H. Anderton. "Tau in Alzheimer's disease and Down's syndrome is insoluble and abnormally phosphorylated." Biochemical Journal 275, no. 1 (April 1, 1991): 99–104. http://dx.doi.org/10.1042/bj2750099.

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Some investigators have described the presence in Alzheimer's disease brain extracts of several abnormal forms of the microtubule-associated protein tau, based on their unusual mobility in SDS/PAGE. It has been proposed that these abnormal forms of tau may be the result of aberrant tau phosphorylation. In this study we show that tau in extracts of Alzheimer's disease brain can be separated into two fractions based upon its solubility (100,000 g x 1 h supernatant) in non-denaturing conditions (100 mM-Mes, pH 6.5, 0.5 mM-MgCl2, 1 mM-EGTA and 1 M-NaCl). The tau isoforms with decreased mobility in SDS/PAGE are predominantly in an insoluble fraction, whereas the soluble tau is indistinguishable by its mobility in SDS/PAGE from tau in soluble extracts of control brain. Insoluble tau displaying abnormal mobility on SDS/PAGE was only found in Alzheimer and adult Down's syndrome brains and was absent from the brains of age-matched controls and from foetal and infant Down's syndrome brains. There was a good correlation between the presence of insoluble tau in brain extracts and the abundance of neurofibrillary tangles and senile neuritic plaques. The monoclonal antibody Tau. 1 stained insoluble tau on Western blots only after treatment of the nitrocellulose transfers with alkaline phosphatase, implying that this insoluble tau is in a particular state of phosphorylation. We conclude that, in Alzheimer's disease, a fraction of tau has a modified phosphorylation state and a decreased solubility; these modifications may precede formation of the neurofibrillary tangles characteristic of Alzheimer's disease and Down's syndrome in adults.

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Lesné, Sylvain E. "Breaking the Code of Amyloid-βOligomers." International Journal of Cell Biology 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/950783.

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Departing from the original postulates that defined various neurodegenerative disorders, accumulating evidence supports a major role for soluble forms of amyloid proteins as initiator toxins in Alzheimer’s disease, Parkinson’s disease, frontotemporal dementias, and prion diseases. Soluble multimeric assemblies of amyloid-β, tau,α-synuclein, and the prion protein are generally englobed under the term oligomers. Due to their biophysical properties, soluble amyloid oligomers can adopt multiple conformations and sizes that potentially confer differential biological activities. Therein lies the problem: with sporadic knowledge and limited tools to identify, characterize, and study amyloid oligomers, how can we solve the enigma of their respective role(s) in the pathogenesis of neurodegenerative disorders? To further our understanding of these devastating diseases, the code of the amyloid oligomers must be broken.

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Moszczynski, Alexander J., Wendy Strong, Kathy Xu, Ann McKee, Arthur Brown, and Michael J. Strong. "Pathologic Thr175 tau phosphorylation in CTE and CTE with ALS." Neurology 90, no. 5 (January 3, 2018): e380-e387. http://dx.doi.org/10.1212/wnl.0000000000004899.

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ObjectiveTo investigate whether chronic traumatic encephalopathy (CTE) and CTE with amyotrophic lateral sclerosis (CTE-ALS) exhibit features previously observed in other tauopathies of pathologic phosphorylation of microtubule-associated protein tau at Thr175 (pThr175 tau) and Thr231 (pThr231 tau), and glycogen synthase kinase–3β (GSK3β) activation, and whether these pathologic features are a consequence of traumatic brain injury (TBI).MethodsTau isoform expression was assayed by western blot in 6 stage III CTE cases. We also used immunohistochemistry to analyze 5 cases each of CTE, CTE-ALS, and 5 controls for expression of activated GSK3β, pThr175 tau, pThr231 tau, and oligomerized tau within spinal cord tissue and hippocampus. Using a rat model of moderate TBI, we assessed tau pathology and phospho-GSK3β expression at 3 months postinjury.ResultsCTE and CTE-ALS are characterized by the presence of all 6 tau isoforms in both soluble and insoluble tau isolates. Activated GSK3β, pThr175 tau, pThr231 tau, and oligomerized tau protein expression was observed in hippocampal neurons and spinal motor neurons. We observed tau neuronal pathology (fibrillar inclusions and axonal damage) and increased levels of pThr175 tau and activated GSK3β in moderate TBI rats.ConclusionsPathologic phosphorylation of tau at Thr175 and Thr231 and activation of GSK3β are features of the tauopathy of CTE and CTE-ALS. These features can be replicated in an animal model of moderate TBI.

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Kawasaki, Ryosuke, and Shin-ichi Tate. "Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments." International Journal of Molecular Sciences 21, no. 11 (May 30, 2020): 3920. http://dx.doi.org/10.3390/ijms21113920.

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Tau forms intracellular insoluble aggregates as a neuropathological hallmark of Alzheimer’s disease. Tau is largely unstructured, which complicates the characterization of the tau aggregation process. Recent studies have demonstrated that tau samples two distinct conformational ensembles, each of which contains the soluble and aggregation-prone states of tau. A shift to populate the aggregation-prone ensemble may promote tau fibrillization. However, the mechanism of this ensemble transition remains elusive. In this study, we explored the conformational dynamics of a tau fragment by using paramagnetic relaxation enhancement (PRE) and interference (PRI) NMR experiments. The PRE correlation map showed that tau is composed of segments consisting of residues in correlated motions. Intriguingly, residues forming the β-structures in the heparin-induced tau filament coincide with residues in these segments, suggesting that each segment behaves as a structural unit in fibrillization. PRI data demonstrated that the P301L mutation exclusively alters the transiently formed tau structures by changing the short- and long-range correlated motions among residues. The transient conformations of P301L tau expose the amyloid motif PHF6 to promote tau self-aggregation. We propose the correlated motions among residues within tau determine the population sizes of the conformational ensembles, and perturbing the correlated motions populates the aggregation-prone form.

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Maté de Gérando, Anastasie, Marie d’Orange, Emma Augustin, Charlène Joséphine, Gwénaelle Aurégan, Mylène Gaudin-Guérif, Martine Guillermier, et al. "Neuronal tau species transfer to astrocytes and induce their loss according to tau aggregation state." Brain 144, no. 4 (April 1, 2021): 1167–82. http://dx.doi.org/10.1093/brain/awab011.

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Abstract Deposits of different abnormal forms of tau in neurons and astrocytes represent key anatomo-pathological features of tauopathies. Although tau protein is highly enriched in neurons and poorly expressed by astrocytes, the origin of astrocytic tau is still elusive. Here, we used innovative gene transfer tools to model tauopathies in adult mouse brains and to investigate the origin of astrocytic tau. We showed in our adeno-associated virus (AAV)-based models and in Thy-Tau22 transgenic mice that astrocytic tau pathology can emerge secondarily to neuronal pathology. By designing an in vivo reporter system, we further demonstrated bidirectional exchanges of tau species between neurons and astrocytes. We then determined the consequences of tau accumulation in astrocytes on their survival in models displaying various status of tau aggregation. Using stereological counting of astrocytes, we report that, as for neurons, soluble tau species are highly toxic to some subpopulations of astrocytes in the hippocampus, whereas the accumulation of tau aggregates does not affect their survival. Thus, astrocytes are not mere bystanders of neuronal pathology. Our results strongly suggest that tau pathology in astrocytes may significantly contribute to clinical symptoms.

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Honisch, Claudia, Federica Torni, Rohanah Hussain, Paolo Ruzza, and Giuliano Siligardi. "Effect of Trehalose and Ceftriaxone on the Stability of Aggregating-Prone Tau Peptide Containing PHF6* Sequence: An SRCD Study." International Journal of Molecular Sciences 23, no. 6 (March 8, 2022): 2932. http://dx.doi.org/10.3390/ijms23062932.

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The tau protein, a soluble protein associated with microtubules, which is involved in the assembly and stabilization of cytoskeletal elements, was found to form neurofibrillary tangles in different neurodegenerative diseases. Insoluble tau aggregates were observed to be organized in paired helical filaments (PHFs) and straight filaments (SFs). Recently, two small sequences (306–311 and 275–280) in the microtubule-binding region (MTBR), named PHF6 and PHF6*, respectively, were found to be essential for tau aggregation. Since a possible therapeutic approach consists of impairing amyloid formation either by stabilizing the native proteins or reducing the level of amyloid precursors, here we use synchrotron radiation circular dichroism (SRCD) at Diamond B23 beamline to evaluate the inhibitory effects of two small molecules, trehalose and ceftriaxone, against the aggregation of a small peptide containing the PHF6* sequence. Our results indicate that both these molecules, ceftriaxone and trehalose, increased the stability of the peptide toward aggregation, in particular that induced by heparin. With trehalose being present in many fruits, vegetables, algae and processed foods, these results support the need to investigate whether a diet richer in trehalose might exert a protective effect toward pathologies linked to protein misfolding.

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Ramser, Elisa M., Kathlyn J. Gan, Helena Decker, Emily Y. Fan, Matthew M. Suzuki, Sergio T. Ferreira, and Michael A. Silverman. "Amyloid-β oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons." Molecular Biology of the Cell 24, no. 16 (August 15, 2013): 2494–505. http://dx.doi.org/10.1091/mbc.e12-12-0858.

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Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD). Soluble amyloid-β oligomers (AβOs), increasingly recognized as proximal neurotoxins in AD, impair organelle transport in cultured neurons and transgenic mouse models. AβOs also stimulate hyperphosphorylation of the axonal microtubule-associated protein, tau. However, the role of tau in FAT disruption is controversial. Here we show that AβOs reduce vesicular transport of brain-derived neurotrophic factor (BDNF) in hippocampal neurons from both wild-type and tau-knockout mice, indicating that tau is not required for transport disruption. FAT inhibition is not accompanied by microtubule destabilization or neuronal death. Significantly, inhibition of calcineurin (CaN), a calcium-dependent phosphatase implicated in AD pathogenesis, rescues BDNF transport. Moreover, inhibition of protein phosphatase 1 and glycogen synthase kinase 3β, downstream targets of CaN, prevents BDNF transport defects induced by AβOs. We further show that AβOs induce CaN activation through nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and demonstrate that tau is not required for AβO-induced BDNF transport disruption.

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Jin, M., N. Shepardson, T. Yang, G. Chen, D. Walsh, and D. J. Selkoe. "Soluble amyloid -protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration." Proceedings of the National Academy of Sciences 108, no. 14 (March 18, 2011): 5819–24. http://dx.doi.org/10.1073/pnas.1017033108.

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Eckert, Anne, Susanne Hauptmann, Isabel Scherping, Virginie Rhein, Franz Müller-Spahn, Jürgen Götz, and Walter E. Müller. "Soluble Beta-Amyloid Leads to Mitochondrial Defects in Amyloid Precursor Protein and Tau Transgenic Mice." Neurodegenerative Diseases 5, no. 3-4 (2008): 157–59. http://dx.doi.org/10.1159/000113689.

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Ondrejcak, Tomas, Igor Klyubin, Grant T. Corbett, Graham Fraser, Wei Hong, Alexandra J. Mably, Matthew Gardener, et al. "Cellular Prion Protein Mediates the Disruption of Hippocampal Synaptic Plasticity by Soluble Tau In Vivo." Journal of Neuroscience 38, no. 50 (October 24, 2018): 10595–606. http://dx.doi.org/10.1523/jneurosci.1700-18.2018.

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Vieira, Marcelo N. N., Letícia Forny-Germano, Leonardo M. Saraiva, Adriano Sebollela, Ana M. Blanco Martinez, Jean-Christophe Houzel, Fernanda G. De Felice, and Sérgio T. Ferreira. "Soluble oligomers from a non-disease related protein mimic Aβ-induced tau hyperphosphorylation and neurodegeneration." Journal of Neurochemistry 103, no. 2 (July 11, 2007): 736–48. http://dx.doi.org/10.1111/j.1471-4159.2007.04809.x.

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Carroll, Trae, Sanjib Guha, Keith Nehrke, and Gail V. W. Johnson. "Tau Post-Translational Modifications: Potentiators of Selective Vulnerability in Sporadic Alzheimer’s Disease." Biology 10, no. 10 (October 15, 2021): 1047. http://dx.doi.org/10.3390/biology10101047.

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Sporadic Alzheimer’s Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles along a well-described path through the brain. This spatial progression provides the basis for Braak staging of the pathological progression for AD. Tau protein is a necessary component of AD pathology, and recent studies have found that soluble tau species with selectively, but not extensively, modified epitopes accumulate along the path of disease progression before AD-associated insoluble aggregates form. As such, modified tau may represent a key cellular stressing agent that potentiates selective vulnerability in susceptible neurons during AD progression. Specifically, studies have found that tau phosphorylated at sites such as T181, T231, and S396 may initiate early pathological changes in tau by disrupting proper tau localization, initiating tau oligomerization, and facilitating tau accumulation and extracellular export. Thus, this review elucidates potential mechanisms through which tau post-translational modifications (PTMs) may simultaneously serve as key modulators of the spatial progression observed in AD development and as key instigators of early pathology related to neurodegeneration-relevant cellular dysfunctions.

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Siano, Giacomo, Chiara Falcicchia, Nicola Origlia, Antonino Cattaneo, and Cristina Di Primio. "Non-Canonical Roles of Tau and Their Contribution to Synaptic Dysfunction." International Journal of Molecular Sciences 22, no. 18 (September 20, 2021): 10145. http://dx.doi.org/10.3390/ijms221810145.

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Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction.

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Hromadkova, Lenka, and Saak Victor Ovsepian. "Tau-Reactive Endogenous Antibodies: Origin, Functionality, and Implications for the Pathophysiology of Alzheimer’s Disease." Journal of Immunology Research 2019 (August 6, 2019): 1–11. http://dx.doi.org/10.1155/2019/7406810.

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In Alzheimer’s disease (AD), tau pathology manifested in the accumulation of intraneuronal tangles and soluble toxic oligomers emerges as a potential therapeutic target. Multiple anti-tau antibodies inhibiting the formation and propagation of cytotoxic tau or promoting its clearance and degradation have been tested in clinical trials, albeit with the inconclusive outcome. Antibodies against tau protein have been found both in the brain circulatory system and at the periphery, but their origin and role under normal conditions and in AD remain unclear. While it is tempting to assign them a protective role in regulating tau level and removal of toxic variants, the supportive evidence remains sporadic, requiring systematic analysis and critical evaluation. Herein, we review recent data showing the occurrence of tau-reactive antibodies in the brain and peripheral circulation and discuss their origin and significance in tau clearance. Based on the emerging evidence, we cautiously propose that impairments of tau clearance at the periphery by humoral immunity might aggravate the tau pathology in the central nervous system, with implication for the neurodegenerative process of AD.

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Feuillette, Sébastien, Laetitia Miguel, Thierry Frébourg, Dominique Campion, and Magalie Lecourtois. "Drosophilamodels of human tauopathies indicate that Tau protein toxicityin vivois mediated by soluble cytosolic phosphorylated forms of the protein." Journal of Neurochemistry 113, no. 4 (May 2010): 895–903. http://dx.doi.org/10.1111/j.1471-4159.2010.06663.x.

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Abdelhamid, Mona, Chunyu Zhou, Cha-Gyun Jung, and Makoto Michikawa. "Probiotic Bifidobacterium breve MCC1274 Mitigates Alzheimer’s Disease-Related Pathologies in Wild-Type Mice." Nutrients 14, no. 12 (June 19, 2022): 2543. http://dx.doi.org/10.3390/nu14122543.

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Probiotics improve brain function, including memory and cognition, via the microbiome–gut–brain axis. Oral administration of Bifidobacterium breve MCC1274 (B. breve MCC1274) improves cognitive function in AppNL-G-F mice and mild cognitive impairment (MCI) subjects, and mitigates Alzheimer’s disease (AD)-like pathologies. However, its effects on wild-type (WT) mice have not yet been explored. Thus, the effects of B. breve MCC1274 on AD-like pathologies in two-month-old WT mice were investigated, which were orally administered B. breve MCC1274 for four months. Aβ levels, amyloid precursor protein (APP), APP processing enzymes, phosphorylated tau, synaptic protein levels, glial activity, and cell proliferation in the subgranular zone of the dentate gyrus were evaluated. Data analysis was performed using Student’s t-test, and normality was tested using the Shapiro–Wilk test. Oral administration of B. breve MCC1274 in WT mice decreased soluble hippocampal Aβ42 levels by reducing presenilin1 protein levels, and reduced phosphorylated tau levels. It also activated the protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway, which may be responsible for the reduction in presenilin1 levels and inhibition of tau phosphorylation. B. breve MCC1274 supplementation attenuated microglial activation and elevated synaptic protein levels in the hippocampus. These findings suggest that B. breve MCC1274 may mitigate AD-like pathologies in WT mice by decreasing Aβ42 levels, inhibiting tau phosphorylation, attenuating neuroinflammation, and improving synaptic protein levels.

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Liu, Zhenzhen, Tao Li, Ping Li, Nannan Wei, Zhiquan Zhao, Huimin Liang, Xinying Ji, Wenwu Chen, Mengzhou Xue, and Jianshe Wei. "The Ambiguous Relationship of Oxidative Stress, Tau Hyperphosphorylation, and Autophagy Dysfunction in Alzheimer’s Disease." Oxidative Medicine and Cellular Longevity 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/352723.

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Alzheimer’s disease (AD) is the most common form of dementia. The pathological hallmarks of AD are amyloid plaques [aggregates of amyloid-beta (Aβ)] and neurofibrillary tangles (aggregates of tau). Growing evidence suggests that tau accumulation is pathologically more relevant to the development of neurodegeneration and cognitive decline in AD patients than Aβplaques. Oxidative stress is a prominent early event in the pathogenesis of AD and is therefore believed to contribute to tau hyperphosphorylation. Several studies have shown that the autophagic pathway in neurons is important under physiological and pathological conditions. Therefore, this pathway plays a crucial role for the degradation of endogenous soluble tau. However, the relationship between oxidative stress, tau protein hyperphosphorylation, autophagy dysregulation, and neuronal cell death in AD remains unclear. Here, we review the latest progress in AD, with a special emphasis on oxidative stress, tau hyperphosphorylation, and autophagy. We also discuss the relationship of these three factors in AD.

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De Strooper, Bart. "Proteases and Proteolysis in Alzheimer Disease: A Multifactorial View on the Disease Process." Physiological Reviews 90, no. 2 (April 2010): 465–94. http://dx.doi.org/10.1152/physrev.00023.2009.

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Alzheimer disease is characterized by the accumulation of abnormally folded protein fragments, i.e., amyloid beta peptide (Aβ) and tau that precipitate in amyloid plaques and neuronal tangles, respectively. In this review we discuss the complicated proteolytic pathways that are responsible for the generation and clearance of these fragments, and how disturbances in these pathways interact and provide a background for a novel understanding of Alzheimer disease as a multifactorial disorder. Recent insights evolve from the static view that the morphologically defined plaques and tangles are disease driving towards a more dynamic, biochemical view in which the intermediary soluble Aβ oligomers and soluble tau fragments are considered as the main mediators of neurotoxicity. The relevance of proteolytic pathways, centered on the generation and clearance of toxic Aβ, on the cleavage and nucleation of tau, and on the general proteostasis of the neurons, then becomes obvious. Blocking or stimulating these pathways provide, or have the potential to provide, interesting drug targets, which raises the hope that we will be able to provide a cure for this dreadful disorder.

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Lemke, Nora, Valeria Melis, Dilyara Lauer, Mandy Magbagbeolu, Boris Neumann, Charles R. Harrington, Gernot Riedel, Claude M. Wischik, Franz Theuring, and Karima Schwab. "Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the line 66 model of frontotemporal dementia." Journal of Biological Chemistry 295, no. 52 (October 30, 2020): 18508–23. http://dx.doi.org/10.1074/jbc.ra120.014890.

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Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that nonphosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, whereas endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilization with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. MS corroborated that synaptosomal tau is nonphosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and nonphosphorylated state, and one that could have a direct impact on cognitive function.

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Natale, Carmina, Maria Monica Barzago, and Luisa Diomede. "Caenorhabditis elegans Models to Investigate the Mechanisms Underlying Tau Toxicity in Tauopathies." Brain Sciences 10, no. 11 (November 11, 2020): 838. http://dx.doi.org/10.3390/brainsci10110838.

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The understanding of the genetic, biochemical, and structural determinants underlying tau aggregation is pivotal in the elucidation of the pathogenic process driving tauopathies and the design of effective therapies. Relevant information on the molecular basis of human neurodegeneration in vivo can be obtained using the nematode Caenorhabditis elegans (C. elegans). To this end, two main approaches can be applied: the overexpression of genes/proteins leading to neuronal dysfunction and death, and studies in which proteins prone to misfolding are exogenously administered to induce a neurotoxic phenotype. Thanks to the easy generation of transgenic strains expressing human disease genes, C. elegans allows the identification of genes and/or proteins specifically associated with pathology and the specific disruptions of cellular processes involved in disease. Several transgenic strains expressing human wild-type or mutated tau have been developed and offer significant information concerning whether transgene expression regulates protein production and aggregation in soluble or insoluble form, onset of the disease, and the degenerative process. C. elegans is able to specifically react to the toxic assemblies of tau, thus developing a neurodegenerative phenotype that, even when exogenously administered, opens up the use of this assay to investigate in vivo the relationship between the tau sequence, its folding, and its proteotoxicity. These approaches can be employed to screen drugs and small molecules that can interact with the biogenesis and dynamics of formation of tau aggregates and to analyze their interactions with other cellular proteins.

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Sayner, Sarah L., Ron Balczon, Dara W. Frank, Dermot M. F. Cooper, and Troy Stevens. "Filamin A is a phosphorylation target of membrane but not cytosolic adenylyl cyclase activity." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 1 (July 2011): L117—L124. http://dx.doi.org/10.1152/ajplung.00417.2009.

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Transmembrane adenylyl cyclase (AC) generates a cAMP pool within the subplasma membrane compartment that strengthens the endothelial cell barrier. This cAMP signal is steered toward effectors that promote junctional integrity and is inactivated before it accesses microtubules, where the cAMP signal causes phosphorylation of tau, leading to microtubule disassembly and barrier disruption. During infection, Pseudomonas aeruginosa uses a type III secretion system to inject a soluble AC, ExoY, into the cytosol of pulmonary microvascular endothelial cells. ExoY generates a cAMP signal that disrupts the endothelial cell barrier. We tested the hypothesis that this ExoY-dependent cAMP signal causes phosphorylation of tau, without inducing phosphorylation of membrane effectors that strengthen endothelial barrier function. To approach this hypothesis, we first discerned the membrane compartment in which endogenous transmembrane AC6 resides. AC6 was resolved in caveolin-rich lipid raft fractions with calcium channel proteins and the cell adhesion molecules N-cadherin, E-cadherin, and activated leukocyte adhesion molecule. VE-cadherin was excluded from the caveolin-rich fractions and was detected in the bulk plasma membrane fractions. The actin binding protein, filamin A, was detected in all membrane fractions. Isoproterenol activation of ACs promoted filamin phosphorylation, whereas thrombin inhibition of AC6 reduced filamin phosphorylation within the membrane fraction. In contrast, ExoY produced a cAMP signal that did not cause filamin phosphorylation yet induced tau phosphorylation. Hence, our data indicate that cAMP signals are strictly compartmentalized; whereas cAMP emanating from transmembrane ACs activates barrier-enhancing targets, such as filamin, cAMP emanating from soluble ACs activates barrier-disrupting targets, such as tau.

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Maron, Ruth, Gad Armony, Michael Tsoory, Meir Wilchek, Dan Frenkel, and Ruth Arnon. "Peptide Interference with APP and Tau Association: Relevance to Alzheimer’s Disease Amelioration." International Journal of Molecular Sciences 21, no. 9 (May 5, 2020): 3270. http://dx.doi.org/10.3390/ijms21093270.

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The two major proteins involved in Alzheimer’s disease (AD) are the amyloid precursor protein (APP) and Tau. Here, we demonstrate that these two proteins can bind to each other. Four possible peptides APP1 (390–412), APP2 (713–730), Tau1 (19–34) and Tau2 (331–348), were predicted to be involved in this interaction, with actual binding confirmed for APP1 and Tau1. In vivo studies were performed in an Alzheimer Disease animal model—APP double transgenic (Tg) 5xFAD—as well as in 5xFAD crossed with Tau transgenic 5xFADXTau (FT), which exhibit declined cognitive reduction at four months of age. Nasal administration of APP1 and Tau1 mixture, three times a week for four or five months, reduced amyloid plaque burden as well as the level of soluble Aβ 1–42 in the brain. The treatment prevented the deterioration of cognitive functions when initiated at the age of three months, before cognitive deficiency was evident, and also at the age of six months, when such deficiencies are already observed, leading to a full regain of cognitive function.

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Pinzi, Luca, Annachiara Tinivella, and Giulio Rastelli. "Chemoinformatics Analyses of Tau Ligands Reveal Key Molecular Requirements for the Identification of Potential Drug Candidates against Tauopathies." Molecules 26, no. 16 (August 20, 2021): 5039. http://dx.doi.org/10.3390/molecules26165039.

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Tau is a highly soluble protein mainly localized at a cytoplasmic level in the neuronal cells, which plays a crucial role in the regulation of microtubule dynamic stability. Recent studies have demonstrated that several factors, such as hyperphosphorylation or alterations of Tau metabolism, may contribute to the pathological accumulation of protein aggregates, which can result in neuronal death and the onset of a number of neurological disorders called Tauopathies. At present, there are no available therapeutic remedies able to reduce Tau aggregation, nor are there any structural clues or guidelines for the rational identification of compounds preventing the accumulation of protein aggregates. To help identify the structural properties required for anti-Tau aggregation activity, we performed extensive chemoinformatics analyses on a dataset of Tau ligands reported in ChEMBL. The performed analyses allowed us to identify a set of molecular properties that are in common between known active ligands. Moreover, extensive analyses of the fragment composition of reported ligands led to the identification of chemical moieties and fragment combinations prevalent in the more active compounds. Interestingly, many of these fragments were arranged in recurring frameworks, some of which were clearly present in compounds currently under clinical investigation. This work represents the first in-depth chemoinformatics study of the molecular properties, constituting fragments and similarity profiles, of known Tau aggregation inhibitors. The datasets of compounds employed for the analyses, the identified molecular fragments and their combinations are made publicly available as supplementary material.

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Zhang, Xiang, Shengnan Zhang, Li Zhang, Jinxia Lu, Chunyu Zhao, Feng Luo, Dan Li, Xueming Li, and Cong Liu. "Heat shock protein 104 (HSP104) chaperones soluble Tau via a mechanism distinct from its disaggregase activity." Journal of Biological Chemistry 294, no. 13 (February 4, 2019): 4956–65. http://dx.doi.org/10.1074/jbc.ra118.005980.

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Perea, Juan Ramón, Marta Bolós, and Jesús Avila. "Microglia in Alzheimer’s Disease in the Context of Tau Pathology." Biomolecules 10, no. 10 (October 14, 2020): 1439. http://dx.doi.org/10.3390/biom10101439.

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Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.

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Kumar, Arvind. "A Review on: Alzheimer’s disease and mechanistic insights of bioactive compounds in its treatment." YMER Digital 21, no. 07 (July 31, 2022): 1297–307. http://dx.doi.org/10.37896/ymer21.07/a9.

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Alzheimer’s disease is a most common neurological disorder, associated with cognitive disorder. Pathologically, Alzheimer's disease is characterized via the presence of β-amyloid (Aβ) plaques, hyper-phosphorylated tau proteins, and neurofibrillary tangles, but persistence oxidative-nitrative stress, endoplasmic reticulum pressure, mitochondrial disorder, inflammatory cytokines, pro-apoptotic proteins in conjunction with altered neurotransmitters degree are common etiological attributes in its pathogenesis. With the modern state of affairs, the variety of published proofs shows the neuroprotective capability of evidently occurring bioactive molecule via their anti-oxidant, ant apoptotic and neutransmitter modulatory residences. Many researchers have counselled that change of life style, proper diet, can delay or prevent the onset of this ailment. Diet is presently considered to be an important component in controlling fitness and protecting oneself towards oxidative strain and persistent inflammation, and hence towards chronic degenerative illnesses. A wide variety of bioactive food compounds may impact the pathological mechanisms underlying AD. Among them, phenolic compounds, omega-three fatty acids, fats-soluble vitamins, isothiocyanates, seem like the best in stopping neurodegeneration. The present review gathers proof that helps the neuroprotective impact of bioactive materials. Keywords: Alzheimer’s disease, neurodegeneration, amyloid cascade, tau protein, tau hypothesis, nitric oxide

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Melo, Ana M., Juliana Coraor, Garrett Alpha-Cobb, Shana Elbaum-Garfinkle, Abhinav Nath, and Elizabeth Rhoades. "A functional role for intrinsic disorder in the tau-tubulin complex." Proceedings of the National Academy of Sciences 113, no. 50 (November 23, 2016): 14336–41. http://dx.doi.org/10.1073/pnas.1610137113.

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Tau is an intrinsically disordered protein with an important role in maintaining the dynamic instability of neuronal microtubules. Despite intensive study, a detailed understanding of the functional mechanism of tau is lacking. Here, we address this deficiency by using intramolecular single-molecule Förster Resonance Energy Transfer (smFRET) to characterize the conformational ensemble of tau bound to soluble tubulin heterodimers. Tau adopts an open conformation on binding tubulin, in which the long-range contacts between both termini and the microtubule binding region that characterize its compact solution structure are diminished. Moreover, the individual repeats within the microtubule binding region that directly interface with tubulin expand to accommodate tubulin binding, despite a lack of extension in the overall dimensions of this region. These results suggest that the disordered nature of tau provides the significant flexibility required to allow for local changes in conformation while preserving global features. The tubulin-associated conformational ensemble is distinct from its aggregation-prone one, highlighting differences between functional and dysfunctional states of tau. Using constraints derived from our measurements, we construct a model of tubulin-bound tau, which draws attention to the importance of the role of tau’s conformational plasticity in function.

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Steen Jensen, Camilla, Erik Portelius, Volkert Siersma, Peter Høgh, Lene Wermuth, Kaj Blennow, Henrik Zetterberg, Gunhild Waldemar, Steen Gregers Hasselbalch, and Anja Hviid Simonsen. "Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease." Dementia and Geriatric Cognitive Disorders 42, no. 3-4 (2016): 146–58. http://dx.doi.org/10.1159/000449408.

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Background: Physical exercise may have some effect on cognition in patients with Alzheimer disease (AD). However, the underlying biochemical effects are unclear. Animal studies have shown that amyloid beta (Aβ), one of the pathological hallmarks of AD, can be altered with high levels of physical activity. Aim: The objective of this study was to elucidate the effect of 16 weeks of moderate- to high-intensity physical exercise on the biomarkers of AD, with special emphasis on the amyloidogenic pathway. Methods: From a total of 53 patients with AD participating in the Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study we analyzed cerebrospinal fluid samples for Aβ species, total tau (t-tau), phosphorylated tau (p-tau) and soluble amyloid precursor protein (sAPP) species. We also assessed the patients for apolipoprotein E ε4 (ApoE ε4) genotype. Results: We found no effect of 16 weeks of physical exercise on the selected biomarkers, and no effect of ApoE ε4 genotype. Conclusion: Our findings suggest that the possible effect of physical exercise on cognition in patients with AD is not due to modulation of Aβ, t-tau, p-tau and sAPP species.

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Bansal, Aditya, Yari Carlomagno, Leonard Petrucelli, Val Lowe, Casey Cook, and Mukesh Pandey. "In-vitro binding assessment of soluble and insoluble tau protein variants with [18F]-AV1451 and [18F]-MK6240." Nuclear Medicine and Biology 108-109 (May 2022): S99—S100. http://dx.doi.org/10.1016/s0969-8051(22)00228-1.

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Bloom, George S., and Andrés Norambuena. "Alzheimer’s disease as a metabolic disorder." OCL 25, no. 4 (July 2018): D403. http://dx.doi.org/10.1051/ocl/2018044.

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Alzheimer’s disease (AD) is defined by memory loss and cognitive impairment, along with the accumulation in brain of two types of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Both plaques and tangles are composed predominantly of poorly soluble filaments that respectively assemble from amyloid-β (Aβ) peptides and the neuron-specific, microtubule-associated protein, tau. It is now widely acknowledged that soluble oligomers of Aβ and tau, the building blocks of plaques and tangles, are principal drivers of AD pathogenesis by acting coordinately to impair and destroy synapses, and kill neurons. The behavioral features of AD are a direct consequence of these attacks on synapses and neuronal viability, which in turn reflect a reduced capacity of AD neurons to utilize energy sources needed to maintain neuronal function and vitality. In other words, AD neurons are starving, even when they may be surrounded by abundant nutrients. Here, we review some of the evidence for the metabolic deficiencies of neurons in AD and how they impact neuronal health.

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Journal articles on the topic 'Soluble tau protein'

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