Selective association of neurogranin gene expression with amyloid and tau pathology in the parahippocampal gyrus in Alzheimer’s disease

Abstract

AbstractBackgroundBrain region‐specific neuronal and synaptic damage is associated with clinical symptomatology and pathogenesis of Alzheimer’s disease (AD). The mechanism underlying such regional vulnerability in AD remains elusive.MethodPublic access datasets from the Mount Sinai NIH NeuroBioBank (MSBB), The Religious order Study and the Memory and Aging Project(ROSMAP) and the Harvard Brain Tissue Resource Center (HBTRC) were used in this study. Using a large‐scale transcriptomic dataset from the prefrontal cortex (BA 10, 261 samples), the superior temporal gyrus (BA 22, 240 samples), the parahippocampal gyrus (BA 36, 215 samples) and the pars opercularis (BA 44, 222 samples) of MBSS post‐mortem brains of AD and normal control subjects, we studied the association of the post‐synaptic protein neurogranin (NRGN) gene expression with amyloid and tau pathology (plaque and tangle counts), clinical dementia scale (CDR), and pathological diagnosis of AD. Integrative gene network analysis was conducted by using a combination of the datasets from three brain banks.ResultWe show that NRGN gene expression in post‐mortem brain is associated with the certainty of pathological diagnosis of AD, and negatively associated with amyloid and tau pathology only in parahippocampal gyrus among the four brain regions examined. NRGN gene expression in parahippocampal gyrus is also negatively associated with CDR scores. Integrative gene network analysis reveals that the positively correlated genes with NRGN in AD are associated with synaptic transmission and cation channel pathways.ConclusionOur results suggest that synaptic damage in selective brain regions contributes to the clinical phenotype in AD. Understanding of synaptic functional pathways associated with synaptic damage may provide another avenue to prioritize targets for AD.