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Exploring CRMP5 as a novel target for Alzheimers disease

探索 CRMP5 作为阿尔茨海默病的新靶点

基本信息

批准号：
10712329
负责人：
Liberty Francois Ep Moutal
金额：
$ 37.77万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-14 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10712329
关键词：
3xTg-AD mouse Acceleration Administrative Supplement Adult Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid deposition Autoantibodies Autopsy Awareness Axon Behavior Behavioral Behavioral Symptoms Biochemical Biochemistry Bioenergetics Biology Brain Breeding Cause of Death Cell Death Cognitive Data Dementia Disease Down-Regulation Economic Burden Electrophysiology (science)Emotional Functional disorder Funding Generations Grant Growth Health Hippocampus Human Human Amyloid Precursor Protein Immunohistochemistry Investments Ion Channel J20 mouse Knock-out Link Long-Term Potentiation Measures Mediator Medicine Memory Memory impairment Mitochondria Mus Mutation N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurites Neurofibrillary Tangles Neurons Pathogenesis Pathologic Patients Peptides Performance Population Positioning Attribute Postsynaptic Membrane Prefrontal Cortex Prevalence Protein Isoforms Proteins Research Risk Role Semaphorin-3A Senile Plaques Signal Transduction Slice Social Behavior Socialization Societies Symptoms Synapses Testing Tissues Transgenic Organisms Tubulin United States Up-Regulation V717F Western Blotting Withdrawal age related aging population cohort dentate gyrus disease phenotype familial Alzheimer disease hyperphosphorylated tau improved knock-down mitochondrial dysfunction morris water maze mouse model neurogenesis neuron loss neurotoxicity new therapeutic target novel object recognition olfactory bulb overexpression painful neuropathy postsynaptic preclinical study programs protein protein interaction response social socioeconomics transcriptome sequencing tubulin polymerization inhibitor β-amyloid burden

项目摘要

ABSTRACT Alzheimer’s disease (AD) is a devastating disease that bears a huge emotional and socio-economic burden. Because of the aging population of our societies, the increasing risks of developing Alzheimer and the lack of proper disease-mitigating strategy, AD is now viewed as a global and urgent crisis. In this proposal, we suggest a new therapeutic target: Collapsin Response Mediator Protein (CRMP)-5, an inhibitor of tubulin polymerization and neurite outgrowth. The rationale here is that targeting proteins that restrict neuronal connectivity of the hippocampus, a prime region of neuronal loss in AD, could prove a valid strategy to mitigate neurotoxicity in AD and decrease its burden. In the hippocampus CRMP5 interacts with tubulin in the growing axon thus halting its growth and negatively regulates neurogenesis. In brains from AD patients, CRMP5 expression is increased in the hippocampus and in the pre-frontal cortex. This supplement builds on the observations that (i) CRMP5 expression was increased in the 3xTg mouse model of AD, (ii) increased CRMP5 expression reduced socialization in 3xTg-AD mice, (iii) CRMP5 knockdown rescued social performance in 3xTg-AD mice, (iv) CRMP5 increases mitochondrial fragmentation, thereby participating in the known dysfunction of mitochondria in the AD brain, (v) CRMP5 controls the post-synaptic expression of GluN2B, an ion channel implicated in AD-induced memory impairment. These results show that CRMP5 upregulation is a pathological feature participating to AD however the function for CRMP5 in the pathogenesis of AD remains unknown. Within this supplement, we will test the effect of CRMP5 knockout on memory impairment and social withdrawal as well as neuronal function in a mouse model of AD. To do so, we will breed a J20 mouse line, which overexpresses human amyloid precursor protein (APP) with two mutations (Swedish and Indiana mutations) linked to familial AD, with our current CRMP5 KO line. We will compare our J20–crmp5-/-compared to J20–crmp5wt mice by evaluating their cognitive behaviors using the novel object recognition and Morris water maze tests and their social behavior using the three-chamber paradigm test. We will assess Aβ burden, as well as synaptic integrity in the hippocampus and pre-frontal cortex. We will also evaluate neuronal loss by immunoblotting using markers of necroptosis, contributing to cell death in human and AD mice models. Mitochondrial dysfunction, an underlying mechanism of AD pathophysiology, will be assessed by cellular bioenergetic profiling and Aβ burden in the mitochondria. Using electrophysiology, we will test synaptic functionality by measuring long-term potentiation (LTP) in hippocampal and prefrontal cortex slices. We expect that knock-down of CRMP5 in the J20 mouse will result in reduced AD phenotypes, defined by (i) increasing memory and social behaviors, (ii) decreasing amyloid plaques burden, (iii) improving mitochondria function, (iv) decreasing neuronal death, and (v) enhancing synaptic integrity and function. This Administrative Supplement request in response to NOT-AG-22-025 will help kickstart a larger and more comprehensive study to evaluate the targeting of CRMP5 to decrease the burden of AD symptoms.

摘要