Auswahl der wissenschaftlichen Literatur zum Thema „Transgenní model TgF344-AD“

Abstract Current findings suggest that accumulation of amyloid-β (Aβ) and hyperphosphorylated tau in the brain disrupt synaptic function in hippocampal–cortical neuronal networks leading to impairment in cognitive and affective functions in Alzheimer’s disease (AD). Development of new disease-modifying AD drugs are challenging due to the lack of predictive animal models and efficacy assays. In the present study we recorded neural activity in TgF344-AD rats, a transgenic model with a full array of AD pathological features, including age-dependent Aβ accumulation, tauopathy, neuronal loss, and cognitive impairments. Under urethane anesthesia, TgF344-AD rats showed significant age-dependent decline in brainstem-elicited hippocampal theta oscillation and decreased theta-phase gamma-amplitude coupling comparing to their age-matched wild-type counterparts. In freely-behaving condition, the power of hippocampal theta oscillation and gamma power during sharp-wave ripples were significantly lower in TgF344-AD rats. Additionally, these rats showed impaired coherence in both intercortical and hippocampal–cortical network dynamics, and increased incidence of paroxysmal high-voltage spindles, which occur during awake, behaviorally quiescent state. TgF344-AD rats demonstrated impairments in sensory processing, having diminished auditory gating and 40-Hz auditory evoked steady-state response. The observed differences in neurophysiological activities in TgF344-AD rats, which mirror several abnormalities described in AD patients, may be used as promising markers to monitor disease-modifying therapies.

The research of Alzheimer’s disease (AD) in its early stages and its progression till symptomatic onset is essential to understand the pathology and investigate new treatments. Animal models provide a helpful approach to this research, since they allow for controlled follow-up during the disease evolution. In this work, transgenic TgF344-AD rats were longitudinally evaluated starting at 6 months of age. Every 3 months, cognitive abilities were assessed by a memory-related task and magnetic resonance imaging (MRI) was acquired. Structural and functional brain networks were estimated and characterized by graph metrics to identify differences between the groups in connectivity, its evolution with age, and its influence on cognition. Structural networks of transgenic animals were altered since the earliest stage. Likewise, aging significantly affected network metrics in TgF344-AD, but not in the control group. In addition, while the structural brain network influenced cognitive outcome in transgenic animals, functional network impacted how control subjects performed. TgF344-AD brain network alterations were present from very early stages, difficult to identify in clinical research. Likewise, the characterization of aging in these animals, involving structural network reorganization and its effects on cognition, opens a window to evaluate new treatments for the disease.

Transgenic modification of the two most common genes (APPsw, PS1ΔE9) related to familial Alzheimer’s disease (AD) in rats has produced a rodent model that develops pathognomonic signs of AD without genetic tau-protein modification. We used 17-month-old AD rats (n = 8) and age-matched controls (AC, n = 7) to evaluate differences in sleep behavior and EEG features during wakefulness (WAKE), non-rapid eye movement sleep (NREM), and rapid eye movement sleep (REM) over 24-h EEG recording (12:12h dark–light cycle). We discovered that AD rats had more sleep–wake transitions and an increased probability of shorter REM and NREM bouts. AD rats also expressed a more uniform distribution of the relative spectral power. Through analysis of information content in the EEG using entropy of difference, AD animals demonstrated less EEG information during WAKE, but more information during NREM. This seems to indicate a limited range of changes in EEG activity that could be caused by an AD-induced change in inhibitory network function as reflected by increased GABAAR-β2 expression but no increase in GAD-67 in AD animals. In conclusion, this transgenic rat model of Alzheimer’s disease demonstrates less obvious EEG features of WAKE during wakefulness and less canonical features of sleep during sleep.

AbstractAmyloid plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Animals were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4 T Bruker scanner. MnCl2 improved signal-to-noise ratio but was not necessary to detect plaques in high-resolution images. Plaques were visible in all transgenic animals and no wild-types, and quantitative susceptibility mapping showed that they were more paramagnetic than the surrounding tissue. This, combined with beta-amyloid and iron staining, indicate that plaque MR visibility in both animal models was driven by plaque size and iron load. Longitudinal relaxation rate mapping revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. This was limited to the rhinencephalon in the TgF344-AD rats, while it was most significantly increased in the cortex of the 5xFAD mice. Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting amyloid plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present the first in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.

Background: Anxious-depressive-like behavior has been recognized as an early endophenotype in Alzheimer’s disease (AD). Recent studies support early treatment of anxious-depressive-like behavior as a potential target to alleviate memory loss and reduce the risk of developing dementia. We hypothesize that photobiomodulation (PBM) could be an effective method to alleviate depression and anxiety at the early stage of AD pathogenesis. Objective: To analyze the effect of PBM treatment on anxious-depressive-like behavior at the early stage of AD. Methods: Using a novel transgenic AD rat model, animals were divided into wild-type, AD+sham PBM, and AD+PBM groups. Two-minute daily PBM (irradiance: 25 mW/cm2 and fluence: 3 J/cm2 at the cortical level) was applied transcranially to the brain of AD animals from 2 months of age to 10 months of age. After completing PBM treatment at 10 months of age, behavioral tests were performed to measure learning, memory, and anxious-depressive-like behavior. Neuronal apoptosis, neuronal degeneration, neuronal damage, mitochondrial function, neuroinflammation, and oxidative stress were measured to test the effects of PBM on AD animals. Results: Behavioral tests showed that: 1) no spatial memory deficits were detected in TgF344 rats at 10 months of age; 2) PBM alleviated anxious-depressive-like behavior in TgF344 rats; 3) PBM attenuated neuronal damage, degeneration, and apoptosis; and 4) PBM suppresses neuroinflammation and oxidative stress. Conclusion: Our findings support our hypothesis that PBM could be an effective method to alleviate depression and anxiety during the early stage of AD development. The mechanism underlying these beneficial effects may be due to the improvement of mitochondria function and integrity and the inhibition of neuroinflammation and oxidative stress.

Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of peoples’ lives worldwide. While the consequences of AD are recognizable, the etiology is unclear. Gene-environment interactions have been implicated in the development of the disease, and exposure to organophosphorus (OPs) compounds is one of the environmental factors associated with AD. Evidence links exposure to levels of OPs encountered in agriculture, horticulture, and other work places with neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Unfortunately, the mechanisms underlying these effects have yet to be established. Here, we set out to examine the long-term consequences of exposure to a commonly applied OP insecticide, chlorpyrifos (CPF), in an attempt to identify a causal link between occupational exposures and chronic illnesses. We exposed a transgenic rodent model of AD, TgF344-AD, to levels of CPF representing occupational exposures and examined ensuing behaviors and neuropathologies. We observed a sex-specific, biphasic response in CPF-exposed animals, including acute neurotoxicities, followed by intermediate recovery, and finally, chronic cognitive impairments. CPF exposure exacerbated neuronal damage in brain regions critical to the impaired behaviors, and neuroinflammatory pathways were identified as facilitators of this damage. This work emphasizes the long-term consequences of early life repeated exposures to OPs and identifies dysregulated microglia as a potential deleterious modifier of disease. Additionally, we investigated the efficacy of a neuroprotective compound, (-)-P7C3-S243 in TgF344-AD rats. P7C3 compounds exert protection by preventing young hippocampal neurons from dying prematurely and also enhancing flux of nicotinamide adenine dinucleotide (NAD), thereby aiding in neuron survival under conditions that normally cause axon degeneration and cell death. These compounds have proven effective in preclinical models of Parkinson’s disease, amyotrophic lateral sclerosis, and traumatic brain injury. Thus, we sought to investigate the neuroprotective efficacy of P7C3 compounds in AD, as well. (-)-P7C3-S243 was administered to wild-type and transgenic male and female rats daily for 9 and 18 months, and classic hallmarks of the disease were assessed. Transgenic rats developed a spectrum of AD pathologies and behaviors, as expected, and (-)-P7C3-S243 ameliorated early depression-like behaviors, late learning and memory deficits, and progressive neuronal damage in this model, without influencing amyloid plaque deposition, tauopathies, or neuroinflammation. This data suggests that targeting neuronal cell death pathways is a promising treatment strategy in AD. Taken together, the research presented here expands our current understanding of pathways of regulation in Alzheimer’s disease—organophosphates are capable of exacerbating the severity of AD, while P7C3 compounds are promising therapeutic candidates for neuronal death in the disease. Given the overlapping molecular pathways of modulation in CPF-induced toxicity and (-)-P7C3-S243 neuroprotection in AD, future studies will investigate the efficacy of (-)-P7C3-S243 in cognitive deficits induced by CPF exposure. Ultimately, this body of work highlights the plasticity of neuronal cell death and cognitive impairment in AD, thus indicating a better understanding of these pathways could facilitate vastly improved intervention strategies in Alzheimer’s disease.

Animal models of Alzheimer's disease display cognitive insufficiencies which mimic human symptoms and occur at a given age or post-treatment time. Animals are typically tested using canonical behavioral tests, lasting minutes and taking place mostly in the non-active period of the daily cycle. Animals are exposed to certain amounts of manipulation-induced stress. Our work represents a validation study for the rat behavioral system IntelliCage. The tested individuals live freely in a group and their behavior is monitored continuously. It is however possible to set up individual tests for each animal or a group of animals. The rats are not subject to human manipulation and hence the results are not affected by manipulation-induced stress. We tested early cognitive impairment in the transgenic rat model TgF344-AD at 6 - 8 months of age. Further, we tested two most common protocols of the streptozotocin model, i.e. single dose of intracerebroventricular 3 mg/kg streptozotocin and double dose 48 hrs apart. Results were compared with the canonical Morris Water Maze (MWM) test. In the MWM test, transgenic animals did not differ from controls in any of the studied parameters. The streptozotocin model displayed a deficit only in the double dose group. However in the IntelliCage, transgenic animals displayed...