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Age, Sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients

ABSTRACT: Aging and sex are major risk factors for developing late-onset Alzheimer’s disease. Compared to men, women are not only nearly twice as likely to develop Alzheimer’s, but they also experience worse neuropathological burden and cognitive decline despite living longer with the disease. It remains unclear how and when sex differences in biological aging emerge and contribute to Alzheimer’s disease pathogenesis. We hypothesized that these differences lead to distinct molecular Alzheimer’s disease signatures in males and females, which could be harnessed for therapeutic and biomarker development. We aged male and female, 3xTg-AD and B6129 control mice across their respective lifespans while longitudinally collecting brain samples. We conducted RNA sequencing analysis on bulk brain tissue and examined differentially expressed genes between 3xTg-AD and B6129 samples and across ages in each sex. 3xTg-AD males experienced an accelerated upregulation of immune-related gene expression in the brain relative to females, especially in genes involved in complement system activation, suggesting distinct inflammatory disease trajectories between the sexes. Our data demonstrate that chronic inflammation and complement activation are associated with increased mortality, revealing that age-related changes in immune response act as a primary driver of sex differences in Alzheimer’s disease trajectories.

ORGANISM(S): Mus musculus

PROVIDER: GSE254970 | GEO | 2024/07/08

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD), the most common age-related neurodegenerative disease, is closely associated with and manifested by neuroinflammation, yet the alteration of immune landscape in AD is largely unknown, preventing a deeper mechanistic understanding of neuroinflammation in AD. Two thirds of AD patients are females, and women have a higher risk of developing AD. Women with AD have more extensive brain histological changes than men with AD, more severe cognitive symptoms, and more severe neurodegeneration, suggesting that the disease affects female and male brains differentially. Despite evident AD sex variance, mechanisms and pathways are still poorly understood. Thus, a focus on sex differences in AD is essential to move the field towards effective interventions and to develop sex-specific therapies. To understand the cellular heterogeneity and disease-associated cellular changes in human AD brain, we performed unbiased massively parallel single nucleus RNA sequencing with postmortem frozen human brain tissues of middle temporal gyrus, a brain cortical region strongly affected by AD. From 12 individuals with and without AD, we isolated brain nuclei by sucrose gradient ultracentrifugation, generated single nucleus libraries with 10x Chromium platform (10x Genomics), and sequenced on NovaSeq6000 S4 sequencer (Illumina). We integrated snRNA-seq data of human brains from these 12 individuals of both Alzheimer’s Disease (AD, Braak Stage V/VI, n = 6) and age-matched healthy controls (HC, Braak Stage I/II, n = 6) by single nucleus analysis using Seurat. After quality control filtering, we profiled and analyzed 64,845 single nucleus transcriptomes, clustered all the cells jointly across the 12 donors that include 6 females and 6 males, and identified and annotated the major cell types of the human brain by interrogating the expression patterns of known gene markers, including neurons, excitatory neurons, inhibitory neurons, astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells, endothelial cells, and pericytes.

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Age, Sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients

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