In Search of Mechanisms to Explain the Sex Difference in Alzheimer's Disease Outcomes
As you may know, there are significant differences in incidence and outcomes of Alzheimer's disease between the sexes. In research, differences of this nature can help in developing a better understanding of which mechanisms are more versus less important in the disease process, and so guide efforts to produce therapies. The biochemistry of the brain is enormously complex, and thus so is the pathology of Alzheimer's disease. It remains the case that decades of research cannot do any better than practical experimentation when it comes to determining which mechanisms cause the most harm. See the present focus on clearance of amyloid-β aggregates from the brain, for example. Only once the necessary immunotherapies existed could the research community determine that amyloid-β aggregates are not as important as hoped in the pathology of the condition.
The focus of today's open access paper is largely the role of inflammatory, dysfunctional microglia in Alzheimer's disease, and whether this provides a sizable contribution to sex differences in disease outcomes. The role of microglia in Alzheimer's disease is a growing area of research interest that seems likely to lead to novel therapies and initial clinical trials in the years ahead. Microglia are innate immune cells of the central nervous system, somewhat analogous to the macrophages found elsewhere in the body. In addition to attacking pathogens and destroying unwanted cells, they are also involved in regeneration and maintenance of nervous system tissue, including some of the changes to neural circuits needed for learning and memory. When microglia become overly inflammatory, it is harmful to the structure and function of the brain.
Alzheimer's disease (AD) presents with a sex bias in which women are at higher risk and exhibit more rapid cognitive decline and brain atrophy compared to men. Microglia play a significant role in the pathogenesis and progression of AD and have been shown to be sexually differentiated in health and disease. Whether and how microglia contribute to the sex differences in AD remains to be elucidated. Herein, we characterized the sex differences in amyloid-beta (Aβ) plaque pathology and microglia-plaque interaction using the 5xFAD mouse model and revealed microglial transcriptomic changes that occur in females and males.
Despite women with symptomatic late-onset AD being in the post-menopausal stage, metabolic and pathological changes are seen prior to menopause. For this reason, and because Aβ pathology develops decades prior to clinical presentation, we focused on two hormonally distinct stages of the female rodent estrous cycle (proestrus and diestrus). Our results showed that Aβ plaque morphology is sexually distinct, with females having greater plaque volume and lower plaque compaction compared to males of the same age. Neuritic dystrophy was also increased in female 5xFAD mice, independent of estrous cycle stage. While microglia transcriptomes were not overtly different at the proestrus or diestrus stages, female 5xFAD microglia upregulated genes involved in glycolytic metabolism, antigen presentation, disease-associated microglia, and microglia neurodegenerative phenotype compared to males, some of which have been previously reported.
In addition, we found a novel female-specific enhancement of IFN signaling in microglia, as evidenced by a striking proportion of differentially expressed type 1 interferon genes characteristic of interferon-responsive microglia (IRM). Finally, we validated our transcriptomic results at the protein level and observed that female 5xFAD mice had an enrichment in Aβ+ IRMs compared to males. Collectively, we show that there are sex-specific alterations in Aβ plaque morphology and that endogenous hormonal fluctuations across the estrous cycle do not overtly affect Aβ pathology or microglial transcriptomic profiles. Furthermore, our study identifies a novel sex-specific enhancement of interferon signaling in female microglia responding to Aβ, which may constitute a new therapeutic target for personalized medicine in AD.