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Tau based Monkey model of Alzheimer's Disease; Structure and Function

基于 Tau 的阿尔茨海默病猴子模型；

基本信息

批准号：
10281031
负责人：
Mark G Baxter
金额：
$ 129.58万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10281031
关键词：
13 year old Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia American Animals Autopsy Behavior Behavior assessment Bilateral Biological Markers Brain Cognition Cognitive Data Data Set Dementia Dependovirus Development Disease Distal Dose Emotional Emotions Face Future Genetic Goals Health Hippocampus (Brain)Human Image Impaired cognition Impairment Inflammation Infusion procedures Injections Liquid substance Macaca mulatta Magnetic Resonance Imaging Measurement Medial Memory Microscopic Modeling Monkeys Nature Nerve Degeneration Neurofibrillary Tangles Pathogenesis Pathologic Pathology Patients Pattern Phase Phylogeny Physiology Plasma Positron-Emission Tomography Process Request for Proposals Rodent Sampling Serum Site Social Behavior Structure Synapses Tauopathies Temporal Lobe Testing Therapeutic Agents Time Translating Validation Viral Work base behavioral impairment behavioral study cognitive task cognitive testing cost design effective therapy entorhinal cortex experience hippocampal atrophy imaging study improved in vivo in vivo imaging memory recognition neocortical neuroinflammation neuron loss neuropathology neuroprotection nonhuman primate novel therapeutics object recognition prevent programs tau Proteins tau aggregation tau expression tau mutation tau-1 therapeutic development therapeutic evaluation therapy design translational model vector

项目摘要

Alzheimer’s disease (AD) is a devastating condition that affects more than 5 million Americans, with a total annual cost of more than $300 billion predicted in 2020. Currently there are no effective treatments to counteract or slow the progression of AD, with promising findings in rodents failing to translate into successful therapies for patients. Monkey models may provide a more powerful translational model. The goal of this proposal is to characterize a monkey model of tau pathology in AD. This is responsive to RFA-AG-21-003 requesting proposals that target the “development, characterization, and validation of suitable new or unconventional mammalian non-murine models of AD that may represent improved translational potential by better replicating pathological features of the disease”. With respect to nonhuman primate (NHP) models of AD, the RFA states explicitly that “NHP have a very high translational value because of their close relationship to humans in terms of phylogeny, genetics, physiology, cognition, emotion, and social behavior”. In this proposal we describe initial findings in a tau-based monkey model of AD and propose a program to fully develop and validate the model by three PIs who have decades of experience on aging and neurodegeneration in NHP models. We have targeted the highly vulnerable entorhinal cortex (ERC) for unilateral infusions of an adeno-associated virus expressing a double tau mutation known to cause tau-related dementia in humans (AAV-P301L/S320F) and characterized neuropathology at 3 and 6 months after viral injection in NHPs. This causes extensive and progressive neuroinflammation and tau-based neuropathology, including end-stage neurofibrillary tangles, in ERC and in hippocampal and neocortical targets of ERC. Preliminary PET imaging in these monkeys displays robust phospho-tau accumulation in the hippocampus. The progressive time course relative to the time of vector injection is a great strength in terms of using this model for therapeutic development. These early studies demonstrate the potential for this model to replicate pathological features of AD in the monkey brain and to capture aspects of pathology that have not been well-modeled in rodents. We propose to do a full, rigorous characterization of this model, including long-term behavioral assessment, in vivo imaging, fluid biomarker assessment, and microscopic analyses. Full characterization of this model, will provide a platform to test therapeutic agents at different points in the disease process.

阿尔茨海默病（AD）是一种毁灭性的疾病，影响了500多万美国人，