Erin G. Reed

Background: Alzheimer’s disease (AD), the most prevalent form of dementia, exhibits a strong sex bias, with women comprising two-thirds of all patients, for reasons that remain unclear. Microglia, as the brain’s resident immune cell, are key players in AD pathogenesis and are increasingly understood as being sex-specific. However, the mechanisms underlying these differences, and how they may in turn contribute to distinct pathogenesis has not been well examined. Therefore, this study aimed to investigate the organizational role of neonatal estradiol (E2) in early-life sex-patterning of microglia for disease onset and progression. Methods: We assessed the effect of neonatal estradiol exposure on microglial and neuronal density, microgliosis, and gene expression related to microglial identity and responses using immunohistochemistry, qPCR, and ProteinSimple Jess on-capillary immunoblotting. Results: We find neonatal estradiol administration influences the expression of genes and proteins involved in inflammation and X chromosome inactivation, without affecting cellular composition of the cortex and hippocampus. Additionally, we observed genotype-dependent changes to the female reproductive cycle in E2 treated 5xFAD females. Conclusions: Overall, the results of the present study provide novel insight into the role of steroid sex hormones in neonatal microglial programing, and how this programming may set the stage for further sex- and disease-linked alterations later in life.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and significant neuropathological changes. Early and accurate diagnosis remains a major challenge, highlighting the need for reliable, minimally invasive biomarkers. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising candidates. Their expression is altered in the brains of AD patients, reflecting disease-specific pathological processes, and they are detectable in peripheral biofluids. However, discrepancies in miRNA profiles between the brain and the circulation, and between patient populations remain a significant limitation, raising questions about their origin, transport across the blood–brain barrier, and their reliability in reflecting central nervous system pathology. This review provides a comprehensive overview of current research comparing miRNA expression profiles in brain tissue and blood in AD, with a focus on their biological relevance, mechanisms of release and transport, and diagnostic potential. We also discuss the challenges associated with cross-tissue variability, methodological inconsistencies, and the need for standardized approaches. Finally, we highlight future directions, including multi-tissue analyses and integration with other noninvasive modalities, to improve the clinical utility of miRNA-based biomarkers in AD.

Alzheimer’s disease (AD) is a neurodegenerative disorder disproportionally affecting women with sex-specific disease manifestations and therapeutic responses. Microglial-mediated inflammation occurs in response to and perpetuates disease processes, and fundamental sex differences in microglia may contribute to these sex biases. Both sex chromosomes and gonad-derived hormones shape immune responses, but their contribution to immune-mediated mechanisms underlying the sex bias in AD is unclear. Crossing the Four Core Genotype (FCG) model to separate sex chromosome and gonad-derived hormone effects to the 5xFAD model, we found the sex chromosome complement impacted microgliosis, neuroinflammation, plaque burden and neuritic dystrophy. Modification of pathology largely correlated with microgliosis, and sex chromosomes and gonad-derived hormones influenced plaque remodeling and microglial CD11c expression. Our results provide potential trajectories for studying and targeting microglial-mediated sex differences and emphasize the complex interplay between sex chromosomes and hormones during AD.

Dementia is an umbrella term used to describe deterioration of cognitive function. It is the seventh leading cause of death and is one of the major causes of dependence among older people globally. Alzheimer’s Disease (AD) contributes to approximately 60–70% of dementia cases and is characterized by the accumulation of amyloid plaques and tau tangles in the brain. Neuroinflammation is now widely accepted as another disease hallmark, playing a role in both the response to and the perpetuation of disease processes. Microglia are brain-resident immune cells that are initially effective at clearing amyloid plaques but contribute to the damaging inflammatory milieu of the brain as disease progresses. Circulating peripheral immune cells contribute to this inflammatory environment through cytokine secretion, creating a positive feedback loop with the microglia. One group of these peripherally derived cytokines acting on microglia is the common cytokine receptor γ chain family. These cytokines bind heterodimer receptors to activate three major signaling pathways: MAPK, PI3K, and JAK/STAT. This perspective will look at the mechanisms of these three pathways in microglia and highlight the future directions of this research and potential therapeutics.

Research into Alzheimer’s Disease (AD) describes a link between AD and the resident immune cells of the brain, the microglia. Further, this suspected link is thought to have underlying sex effects, although the mechanisms of these effects are only just beginning to be understood. Many of these insights are the result of policies put in place by funding agencies such as the National Institutes of Health (NIH) to consider sex as a biological variable (SABV) and the move towards precision medicine due to continued lackluster therapeutic options. The purpose of this review is to provide an updated assessment of the current research that summarizes sex differences and the research pertaining to microglia and their varied responses in AD.

Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. In aging and neurodegenerative diseases generally, and Alzheimer’s disease (AD) specifically, microglial function is altered in ways that significantly diverge from their homeostatic state, inducing a more detrimental inflammatory environment. In this review, we discuss the receptors, signaling, regulation and gene expression patterns of microglia that mediate their phenotype and function contributing to the inflammatory milieu of the AD brain, as well as strategies that target microglia to ameliorate the onset, progression and symptoms of AD.

Alzheimer’s disease (AD) is accompanied by a robust inflammatory response mediated by plaque-associated myeloid cells of the brain. These cells exhibit altered gene expression profiles and serve as a barrier, preventing neuritic dystrophy. The origin of these cells has been controversial and is of therapeutic importance. Here, we genetically labeled different myeloid populations and unequivocally demonstrated that plaque-associated myeloid cells in the AD brain are derived exclusively from resident microglia, with no contribution from circulating peripheral monocytes.