Research Project
10126377
Summary Dementia and Alzheimer?s disease (AD) affect hundreds of millions of people in the US and worldwide, after several decades of intensive investigations clinical treatments of these age-related disorders are still very limited. Previous investigations using animal models established on the amyloid beta (A?) and Tau hypothesis have helped to gain extensive knowledge on the pathological features and progression of AD related dementia. Unfortunately, clinical trials directly targeting A? and Tau pathology have so far failed clinical translation. On the other hand, hyperactivation of N-Methyl-D-aspartate receptors (NMDARs) has been identified as a key mechanism contributing to AD pathology and pathogenesis. The NMDAR antagonist memantine is one of few treatments showing some therapeutic benefits for moderate/severe AD and dementia patients. In fact, pharmacological suppression of glutamatergic activities has become an important strategy in postponing A?- induced neuronal damage and AD progression. The research in NMDAR regulations, however, has been heavily focused on the NMDAR subunits GluN1 and GluN2, there is no information about the role of GluN3A in AD related mechanism. As a unique inhibitory subunit of NMDARs, GluN3 keeps the tonic NMDAR activity and chronic Ca2+ homeostasis within the physiological range. Deletion of GluN3A in the knockout (KO) mouse resulted in enhanced neuronal cell death and anxiety behaviors at adult ages. Our preliminary data show that GluN3A KO mice undergo spontaneous evolvement of AD-like pathology and cognitive deficits with aging, which can be prevented by daily treatments of low-dose memantine initiated from the pre-onset stage. In this R21 investigation, we will verify the pathogenic role of GluN3A in age-dependent manners. Specific Aim 1 will characterize the pathological features of the age-dependent dementia and the relation to Alzheimer?s disease. In GluN3A KO and WT mice of different ages, we will examine A? plagues, NFT, phosphorylation of Tau protein, synaptic structures and cell death in the hippocampus and cortex. Inflammatory reactions including reactive astrocytes, microglia/microphage, and inflammatory factors will be measure. Specific Aim 2 will delineate the critical time window for the role of GluN3A in progression of AD-associated pathophysiology. We will perform loss-of-function experiments of conditional GluN3A knockout at different ages to understand whether there is a critical time point for initiating the age-dependent evolvement of dementia and AD pathophysiology. This R21 investigation is the first effort in revealing a regulatory/pathogenic role of the NMDAR subunit GluN3A in age-related dementia and possibly a sporadic AD mouse model. This exploratory study will allow us to develop an evidence-based systematic investigation on the GluN3A-regulated mechanism of dementia and AD pathology. Our ultimate goal is to identify GluN3A as a novel therapeutic target and develop early genetic and pharmacological interventions for an optimal NMDAR regulation in order to delay or even prevent the gradually evolved dementia and the progression of AD pathophysiology.
