A molecular network of the aging brain implicatesINPPL1andPLXNB1in Alzheimer’s disease

Abstract

One sentence summary: Molecular network analysis of RNA sequencing data from the aging human cortex identifies new Alzheimer's and cognitive decline genes.material for any purpose without crediting the original authors.was not peer-reviewed) in the Public Domain. It is no longer restricted by copyright. Anyone can legally share, reuse, remix, or adapt thisThe copyright holder has placed this preprint (which . http://dx.doi.org/10.1101/205807 doi: bioRxiv preprint first posted online 2 AbstractThe fact that only symptomatic therapies of small effect are available for Alzheimer's disease (AD) today highlights the need for new therapeutic targets with which to prevent a major contributor to aging-related cognitive decline. Here, we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first identify the role of modules of coexpressed genes, and then confirm them in independent AD datasets. Then, we prioritize influential genes in AD-related modules and test our predictions in human model systems. We functionally validate two putative regulator genes in human astrocytes: INPPL1 and PLXNB1, whose activity in AD may be related to semaphorin signalling and type II diabetes, which have both been implicated in AD. This arc of network identification followed by statistical and experimental validation provides specific new targets for therapeutic development and illustrates a network approach to a complex disease.

Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia

“…These experiments provided functional validation that the INPPL1 and PLXNB1 genes may play an important role in mediating m109’s effect on β-amyloid metabolism. Much of the variance in cognitive decline explained by m109 remains unexplained after we account for the effect of PLXNB1 and INPPL1 , supporting the network finding that some genes in this network influence cognitive decline independent of AD pathology 3 .…”

“…Our network approach identified m109, that is, the module most proximal to cognitive decline 3 . Our two validation strategies have confirmed the importance of this set of genes and are beginning to dissect a series of correlated transcriptional programs involved in cognition.…”

“…and the burden of brain b-amyloid deposition, the pathological hallmark of Alzheimer's disease (AD), as well as decline in cognition, the clinical hallmark of Alzheimer's dementia. 3 This group of coexpressed genes, arbitrarily labeled module 109 (m109), represents a cortical transcriptional program that is the most proximal molecular event occurring before cognitive decline in aging. Furthermore, our previous modeling suggests that m109 is causally implicated in Alzheimer's dementia through two independent mechanisms: a minor effect on brain-amyloid deposition and a major effect that is independent of b-amyloid and other pathologies.…”

“…Furthermore, our previous modeling suggests that m109 is causally implicated in Alzheimer's dementia through two independent mechanisms: a minor effect on brain-amyloid deposition and a major effect that is independent of b-amyloid and other pathologies. 3 The m109 consists of 390 genes, and we prioritized 30 unique nodal genes as potential drivers of the network's biological function. In an initial round of functional validation, we tested 21 of these 30 genes in human astrocytes and/or human neurons derived from induced pluripotent stem cell.…”

“…Much of the variance in cognitive decline explained by m109 remains unexplained after we account for the effect of PLXNB1 and INPPL1, supporting the network finding that some genes in this network influence cognitive decline independent of AD pathology. 3 In this study, we used selection reaction monitoring (SRM) quantitative proteomics to quantify protein levels of 12 of the nodal genes within m109 ( Fig F1 1). With these data, we extended our previous findings in two ways.…”