Sex Differences in Alzheimer's Disease: Insights From the Multiomics Landscape.

Alzheimer's disease (AD) has complex etiologies, and the impact of sex on AD varies over the course of disease development. The literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex-biased differences in AD remain elusive. Multiomics data in tandem with systems biology approaches offer a new avenue to dissect sex-stratified molecular mechanisms of AD and to develop sex-specific diagnostic and therapeutic strategies for AD. Single-cell transcriptomic datasets and cell deconvolution of bulk tissue transcriptomic data provide additional insights into brain cell type-specific impact on sex-biased differences in AD. In this review, we summarize the impact of sex chromosomes and sex hormones on AD, the impact of sex-biased differences during AD development, and the interplay between sex and a major AD genetic risk factor, the APOE ε4 genotype, through the multiomics landscape. Several sex-biased molecular pathways such as neuroinflammation and bioenergetic metabolism have been identified. The importance of sex chromosome and sex hormones, as well as the associated pathways in AD pathogenesis, is further strengthened by findings from omics studies. Future research efforts should integrate the multiomics data from different brain regions and different cell types using systems biology approaches, and leverage the knowledge into a holistic examination of sex differences in AD. Advances in systems biology technologies and increasingly available large-scale multiomics datasets will facilitate future studies dissecting such complex signaling mechanisms to better understand AD pathogenesis in both sexes, with the ultimate goals of developing efficacious sex- and APOE-stratified preventive and therapeutic interventions for AD.

Endo-lysosomal pathway and ubiquitin-proteasome system dysfunction in Alzheimer's disease pathogenesis.

Several lines of evidence have shown that defects in the endo-lysosomal autophagy degradation pathway and the ubiquitin-proteasome system play a role in Alzheimer's Disease (AD) pathogenesis and pathophysiology. Early pathological changes, such as marked enlargement of endosomal compartments, gradual accumulation of autophagic vacuoles (AVs) and lysosome dyshomeostasis, are well-recognized in AD. In addition to these pathological indicators, many genetic variants of key regulators in the endo-lysosomal autophagy networks and the ubiquitin-proteasome system have been found to be associated with AD. Furthermore, altered expression levels of key proteins in these pathways have been found in AD human brain tissues, primary cells and AD mouse models. In this review, we discuss potential disease mechanisms underlying the dysregulation of protein homeostasis governing systems. While the importance of two major protein degradation pathways in AD pathogenesis has been highlighted, targeted therapy at key components of these pathways has great potential in developing novel therapeutic interventions for AD. Future investigations are needed to define molecular mechanisms by which these complex regulatory systems become malfunctional at specific stages of AD development and progression, which will facilitate future development of novel therapeutic interventions. It is also critical to investigate all key components of the protein degradation pathways, both upstream and downstream, to improve our abilities to manipulate transport pathways with higher efficacy and less side effects.

ApoE4-associated phospholipid dysregulation contributes to development of Tau hyper-phosphorylation after traumatic brain injury.

The apolipoprotein E4 (ApoE4) genotype combines with traumatic brain injury (TBI) to increase the risk of developing Alzheimer's Disease (AD). However, the underlying mechanism(s) is not well-understood. We found that after exposure to repetitive blast-induced TBI, phosphoinositol biphosphate (PIP2) levels in hippocampal regions of young ApoE3 mice were elevated and associated with reduction in expression of a PIP2 degrading enzyme, synaptojanin 1 (synj1). In contrast, hippocampal PIP2 levels in ApoE4 mice did not increase after blast TBI. Following blast TBI, phospho-Tau (pTau) levels were unchanged in ApoE3 mice, whereas in ApoE4 mice, levels of pTau were significantly increased. To determine the causal relationship between changes in pTau and PIP2/synj1 levels after TBI, we tested if down-regulation of synj1 prevented blast-induced Tau hyper-phosphorylation. Knockdown of synj1 decreased pTau levels in vitro, and abolished blast-induced elevation of pTau in vivo. Blast TBI increased glycogen synthase kinase (GSK)-3ß activities in ApoE4 mice, and synj1 knockdown inhibited GSK3ß phosphorylation of Tau. Together, these data suggest that ApoE proteins regulate brain phospholipid homeostasis in response to TBI and that the ApoE4 isoform is dysfunctional in this process. Down-regulation of synj1 rescues blast-induced phospholipid dysregulation and prevents development of Tau hyper-phosphorylation in ApoE4 carriers.