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Age-Related Changes in Neural Network Activity and Tau in a rat model of Alzheimer's Disease

阿尔茨海默病大鼠模型中神经网络活动和 Tau 蛋白与年龄相关的变化

基本信息

批准号：
9530214
负责人：
David H Farb
金额：
$ 24.73万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9530214
关键词：
Acute Adult Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Bioavailable Biological Neural Networks Blood Brain Cells Chronic Custom Data Data Analyses Decision Making Deposition Deterioration Disease Management Disease Marker Disease Progression Dose Early Onset Familial Alzheimer&apos s Disease Electrophysiology (science)Enhancers Environment Exhibits Experimental Designs Food Foundations Functional disorder Future GABA-A Receptor Gene Expression Genes Hippocampus (Brain)Home environment Human Human Pathology Hyperactive behavior Impaired cognition Impairment Implant Mammals Measures Memory Memory Loss Memory impairment Methods Microelectrodes Modeling Molecular Monitor Mutation Nerve Degeneration Neurofibrillary Tangles Neuromodulator Oral Pathologic Pathology Patients Pattern Pharmaceutical Preparations Plasma Procedures Pyramidal Cells Quality of life Rattus Reproducibility Research Personnel Rodent Running Senile Plaques Series System Technology Therapeutic Time Tissues Transgenic Model Transgenic Organisms Treatment Efficacy Work age related aged amnestic mild cognitive impairment base brain dysfunction computerized data processing density gene product improved in vivo male mild cognitive impairment morris water maze mutant neural circuit neurofibrillary tangle formation neuropathology novel presenilin-1 presenilin-2 prevent receptor spatial memory symptom treatment tau Proteins tau-1 tool

项目摘要

Abstract: The devastating progression of Alzheimer's disease (AD) from the early prodromal to late stages has stimulated a search for drugs that prevent this progression and a quest for drugs that can treat the symptoms of memory loss to improve the quality of life even in the face of decline. We hypothesize that determining the effect of AD progression on the dynamic activity of important local circuits in the rodent hippocampus, the tri-synaptic circuit known to underlie spatial memory, will produce an early indicator of brain dysfunction that is more relevant for the discovery of drugs that will work in humans, especially given the conservation of this circuit in all mammals. The firing patterns of CA3 & CA1 pyramidal cells (or “place cells”) within the hippocampus respond to and encode spatial representations. Our previous in vivo electrophysiological study of aged impaired rats, a model for amnestic cognitive impairment (aMCI), demonstrated that we are able to quantify age and novelty specific effects of drugs on CA3 & CA1 place cell dynamics and on spatial memory (Robitsek 2015). In this application, we propose to use an exciting new rat model for AD (TgF344-AD) that displays amyloid plaques and, importantly, neurofibrillary tangles to determine how the progression of pathology seen in human patients is associated with alterations in hippocampal place cell dynamics over time. In addition, we will probe the acute effects of a GABA- A receptor negative allosteric modulator selective for tonically active alpha5 subunit containing receptors that is a memory enhancer on place cell dynamics. We will use high density in vivo electrophysiology for monitoring “place cell” function with age in this novel rat transgenic model to ask the following questions: When does the tri- synaptic circuit become disturbed? Is early disturbance associated with P-tau and neurofibrillary tangle formation, or is it independent? Is there a distinct part of the hippocampal tri-synaptic circuitry that is most vulnerable during disease progression? And finally, can we begin to explain the mechanism by which a negative allosteric modulator of active inhibitory receptors results in spatial memory enhancement. We anticipate that completion of these studies will identify the activity profile of CA3 & CA1 place cells in AD rats that eventually leads to a loss in memory and spread of neuropathology. These studies will be a first step toward elucidating the onset of neural circuitry dysfunction underlying spatial memory decline over a human APP695 and PS1 background that exhibits progressive neurofibrillary tangles and cognitive impairment and will provide a foundation for improved assessment for acute administration of memory enhancers in AD management.

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