Alzheimer's disease (AD) is the most common cause of dementia, afflicting millions of people including the aging populations of veterans. It is extremely important and urgent to find pathophysiological basis and potential treatment for this devastating disease. AD has two prominent features: (1) a selective loss of basal forebrain (BF) cholinergic neurons and cholinergic deficits in cortical areas that lead to cognitive impairment;(2) the accumulation and aggregation of excessive ?-amyloid peptides (A?), which triggers a complex cascade that leads to synaptic alterations and neural injury. Our goal of this proposal is to understand how BF cholinergic neurons are selectively degenerated in AD, and whether it is triggered by A?. BF receives intensive glutamatergic inputs, and BF cholinergic neurons are particularly vulnerable to glutamate excitotoxicity from overactivation of NMDA receptors. One of the metabotropic glutamate receptors, mGluR7, displays a remarkably low affinity for glutamate, thus has been suggested to serve as an """"""""emergency"""""""" receptor to inhibit glutamatergic transmission under pathophysiological conditions. We hypothesize that activation of mGluR7 causes the suppression of NMDAR responses in BF, and A? selectively disrupts mGluR7 inhibition of NMDAR signaling in BF cholinergic neurons. Consequently, the mGluR7-mediated protection against NMDA excitotoxicity is abrogated by A? selectively in BF cholinergic neurons. To test this hypothesis, we will use the combined electrophysiological, pharmacological, biochemical and molecular biological approaches to address two specific aims: (1) To study mGluR7 regulation of NMDAR trafficking &function in BF and the underlying mechanism. (2) To study A?-induced selective impairment of mGluR7 effects on NMDARs in BF cholinergic neurons and the underlying mechanism. Knowledge gained from this study will provide important information linking several key components critically involved in the pathophysiology of AD, including acetylcholine system, A? and NMDA receptors. Not only will it offer significant insights into the cellular and molecular basis of AD, particularly the potential mechanism for the selective vulnerability of BF cholinergic neurons in AD, but also it will help identify new therapeutic targes for AD treatment, such as mGluR7 and regulators of cytoskeleton dynamics involved in mGluR7 signaling.

Public Health Relevance

Alzheimer's disease (AD), the most common cause of dementia, afflicts millions of people including the aging populations of veterans. This study aims to understand the molecular mechanism underlying the selective degeneration of basal forebrain (BF) cholinergic neurons, a prominent feature of the early stage of AD. We hypothesize that activation of the metabotropic glutamate receptor mGluR7 suppresses NMDA receptor trafficking and function in BF and A? selectively disrupts mGluR7 inhibition of NMDA signaling in BF cholinergic neurons, which causes the selective vulnerability of these neurons in AD. Knowledge gained from this study will not only offer significant insights into the cellular and molecular basis of AD, but also help identify new therapeutic targets for AD treatment, such as mGluRs and regulators of mGluR signaling.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology D (NURD)
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VA Western New York Healthcare System
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Zhong, Ping; Hu, Zhixing; Jiang, Houbo et al. (2017) Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations. Cell Rep 19:1033-1044
Xu, Z; Jiang, H; Zhong, P et al. (2016) Direct conversion of human fibroblasts to induced serotonergic neurons. Mol Psychiatry 21:62-70
Wei, Jing; Xiong, Zhe; Lee, Janine B et al. (2016) Histone Modification of Nedd4 Ubiquitin Ligase Controls the Loss of AMPA Receptors and Cognitive Impairment Induced by Repeated Stress. J Neurosci 36:2119-30
Tang, Bo; Luo, Dong; Yang, Jie et al. (2015) Modulation of AMPA receptor mediated current by nicotinic acetylcholine receptor in layer I neurons of rat prefrontal cortex. Sci Rep 5:14099
Jiang, Houbo; Xu, Zhimin; Zhong, Ping et al. (2015) Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons. Nat Commun 6:10100
Hu, Zhixing; Pu, Jiali; Jiang, Houbo et al. (2015) Generation of Naivetropic Induced Pluripotent Stem Cells from Parkinson's Disease Patients for High-Efficiency Genetic Manipulation and Disease Modeling. Stem Cells Dev 24:2591-604
Yuen, Eunice Y; Qin, Luye; Wei, Jing et al. (2014) Synergistic regulation of glutamatergic transmission by serotonin and norepinephrine reuptake inhibitors in prefrontal cortical neurons. J Biol Chem 289:25177-85
Gu, Zhenglin; Cheng, Jia; Zhong, Ping et al. (2014) A? selectively impairs mGluR7 modulation of NMDA signaling in basal forebrain cholinergic neurons: implication in Alzheimer's disease. J Neurosci 34:13614-28
Deng, Yulei; Xiong, Zhe; Chen, Paul et al. (2014) ?-amyloid impairs the regulation of N-methyl-D-aspartate receptors by glycogen synthase kinase 3. Neurobiol Aging 35:449-59
Cheng, Jia; Liu, Wenhua; Duffney, Lara J et al. (2013) SNARE proteins are essential in the potentiation of NMDA receptors by group II metabotropic glutamate receptors. J Physiol 591:3935-47