432.2 - Association of Mouse Vulnerability to Alzheimer’s Disease Pathology with Mutations of Gnb5: A Modulator of G-protein Coupled Receptor Signaling

Emma Fikse (National Institutes of Health), Jianhua Zhang (National Institutes of Health), Mritunjay Pandey (National Institutes of Health), Glenda Smerin (National Institutes of Health), Adam Awe (National Institutes of Health), Nicole Lue (National Institutes of Health), Claire Kittock (National Institutes of Health), Weiping Chen (National Institutes of Health), Yanqin Yang (National Institutes of Health), Poorni Adikaram (National Institutes of Health), Nirmal Jacob (National Institutes of Health), Emily Greenfest-Allen (University of Pennsylvania Perelman School of Medicine), Rachel Thomas (National Institutes of Health), Laura Bomeny (National Institutes of Health), Xiaowen Wang (Partek Incorporated), Yulong Li (National Institutes of Health), William Simonds (National Institutes of Health)

The prevalence and devastating effects of Alzheimer’s Disease (AD) and lack of effective treatments underscore the need to determine genes and molecular pathways with pathophysiologic relevance to develop targeted therapies. Prior unpublished bioinformatic analysis by our laboratory of genomic and brain transcript expression data from subjects with and without AD has identified hundreds of potential AD causative genes, one being GNB5, which encodes the protein Gβ5. Gβ5 is a divergent member of the G-protein β subunit family and is primarily expressed in neuronal tissues. It is known to stabilize members of the R7-Regulator of G-protein Signaling (RGS) subfamily that exert GTPase Accelerating Protein (GAP) activities on Gαi/o proteins during G-protein coupled receptor (GPCR) signaling. Homozygous lack of Gβ5 causes significant neuronal and behavioral impairments in both mice and humans; however, the impact of GNB5 heterozygosity requires further examination. For this project, we demonstrated through fear conditioning behavioral tasks involving hippocampus and amygdala function that learning and memory deficits existed in mice heterozygous for Gnb5. In addition, the potential relevance of GNB5 in AD pathogenesis was confirmed in an APP/PSEN1 double transgenic AD mouse model in which missing even one copy of the Gnb5 gene enhanced amyloid plaque and neurofibrillary tangle formations in multiple brain regions of mice including, the entorhinal cortex, hippocampus, and frontal cortex. These results were confirmed by traditional immunohistochemistry methods as well as immunostaining of transparent mouse brains cleared using the clear, unobstructed brain/body imaging cocktails and computational analysis (CUBIC) method. We further demonstrated that the exacerbated AD pathology may be caused, at least in part, by the increased vulnerability of heterozygous GNB5 mouse neurons to the toxicity of Aβ42 peptide oligomers which have been linked to beta-amyloid plaque formation. Our data suggest the involvement of GNB5 regulated GPCR signaling in the progression of AD pathology and illustrates a potential new therapeutic target for attenuation of cellular pathology associated with AD.

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