Sex-specific transcriptional rewiring in the brain of Alzheimer’s disease patients

Abstract

Sex-specific differences may contribute to Alzheimer’s disease (AD) development. AD is more prevalent in women worldwide, and female sex has been suggested as a disease risk factor. Nevertheless, the molecular mechanisms underlying sex-biased differences in AD remain poorly characterized. To this end, we analyzed the transcriptional changes in the entorhinal cortex of symptomatic and asymptomatic AD patients stratified by sex. Co-expression network analysis implemented by SWItchMiner software identified sex-specific signatures of switch genes responsible for drastic transcriptional changes in the brain of AD and asymptomatic AD individuals. Pathway analysis of the switch genes revealed that morphine addiction, retrograde endocannabinoid signaling, and autophagy are associated with both females with AD (F-AD) and males with (M-AD). In contrast, nicotine addiction, cell adhesion molecules, oxytocin signaling, adipocytokine signaling, prolactin signaling, and alcoholism are uniquely associated with M-AD. Similarly, some of the unique pathways associated with F-AD switch genes are viral myocarditis, Hippo signaling pathway, endometrial cancer, insulin signaling, and PI3K-AKT signaling. Together these results reveal that there are many sex-specific pathways that may lead to AD. Approximately 20–30% of the elderly have an accumulation of amyloid beta in the brain, but show no cognitive deficit. Asymptomatic females (F-asymAD) and males (M-asymAD) both shared dysregulation of endocytosis. In contrast, pathways uniquely associated with F-asymAD switch genes are insulin secretion, progesterone-mediated oocyte maturation, axon guidance, renal cell carcinoma, and ErbB signaling pathway. Similarly, pathways uniquely associated with M-asymAD switch genes are fluid shear stress and atherosclerosis, FcγR mediated phagocytosis, and proteoglycans in cancer. These results reveal for the first time unique pathways associated with either disease progression or cognitive resilience in asymptomatic individuals. Additionally, we identified numerous sex-specific transcription factors and potential neurotoxic chemicals that may be involved in the pathogenesis of AD. Together these results reveal likely molecular drivers of sex differences in the brain of AD patients. Future molecular studies dissecting the functional role of these switch genes in driving sex differences in AD are warranted.

Co-Expression Network Analysis Identifies Molecular Determinants of Loneliness Associated with Neuropsychiatric and Neurodegenerative Diseases

“…For example, depressed men reported higher rates of anger attacks, aggression, substance abuse, and risk-taking than women [ 90 ]. Moreover, male-specific transcriptional rewiring of genes involved in alcohol and cocaine addiction has been recently identified in AD patients ([ 91 ]).…”

CSF proteomic profiling with amyloid/tau positivity identifies distinctive sex-different alteration of multiple proteins involved in Alzheimer’s disease

“…9, 20-24 Male-specific signatures were identified for expression of long noncoding RNAs, or nicotine addiction, adipo-cytokine signaling, and alcoholism as enriched pathways in association with AD in brain. 23, 25…”

“…18 19 Besides sex hormones, female-specific signatures seem to be enriched in immune response, inflammatory signaling pathways, and neuroinflammation in AD in brain and blood. 9,[20][21][22][23][24] Male-specific signatures were identified for expression of long noncoding RNAs, or nicotine addiction, adipo-cytokine signaling, and alcoholism as enriched pathways in association with AD in brain. 23,25 In contrast to the findings from genomic and transcriptomic studies, the impact of sex on proteomic signatures of AD are vastly understudied.…”

“…9,[20][21][22][23][24] Male-specific signatures were identified for expression of long noncoding RNAs, or nicotine addiction, adipo-cytokine signaling, and alcoholism as enriched pathways in association with AD in brain. 23,25 In contrast to the findings from genomic and transcriptomic studies, the impact of sex on proteomic signatures of AD are vastly understudied. Some small scale protein studies in blood reported female-specific results, including tropomyosin-1 protein that is significantly higher in AD females compared to AD or mild cognitive impairment (MCI) males and alpha-2 macroglobin that shows strong correlation with AD progression in females.…”

Sex- and region-specific cortical and hippocampal whole genome transcriptome profiles from control and APP/PS1 Alzheimer’s disease mice

“…However, many of these studies, e.g., in APP/PS1 mice, encounter specific limitations: (i) female and male animals were pooled (in a balanced or unbalanced way) and were not investigated in a sex-specific manner or there was no information provided about the sex distribution [37][38][39][40], (ii) only one sex (generally males) was studied [41][42][43], (iii) the entire brain was investigated and not individual BROIs, although different brain regions can be differentially affected by AD pathogenesis [38]. Thus, the complex sex-and region-specific investigation of transcriptomes of AD models such as APP/PS1 mice, is mandatory [36,[44][45][46].…”