APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition.

The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with low tau pathology and slowdown of cognitive decline despite the causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier1. However, the molecular effects enabling E3S/S mutation to confer protection remain unclear. Here, we replaced mouse Apoe with wild-type human E3 or E3S/S on a tauopathy background. The R136S mutation markedly mitigated tau load and protected against tau-induced synaptic loss, myelin loss, and spatial learning. Additionally, the R136S mutation reduced microglial interferon response to tau pathology both in vivo and in vitro, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type E3 with cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the R136S mutation across brain cell types. Thus, cGAS-STING-IFN inhibition recapitulates the protective effects of R136S against tauopathy.

Mechanisms of sex differences in Alzheimer's disease.

Alzheimer's disease (AD) and the mechanisms underlying its etiology and progression are complex and multifactorial. The higher AD risk in women may serve as a clue to better understand these complicated processes. In this review, we examine aspects of AD that demonstrate sex-dependent effects and delve into the potential biological mechanisms responsible, compiling findings from advanced technologies such as single-cell RNA sequencing, metabolomics, and multi-omics analyses. We review evidence that sex hormones and sex chromosomes interact with various disease mechanisms during aging, encompassing inflammation, metabolism, and autophagy, leading to unique characteristics in disease progression between men and women.

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

Sex Chromosomes and Gonads Shape the Sex-Biased Transcriptomic Landscape in Tlr7-Mediated Demyelination During Aging.

Demyelination occurs in aging and associated diseases, including Alzheimer's disease. Several of these diseases exhibit sex differences in prevalence and severity. Biological sex primarily stems from sex chromosomes and gonads releasing sex hormones. To dissect mechanisms underlying sex differences in demyelination of aging brains, we constructed a transcriptomic atlas of cell type-specific responses to illustrate how sex chromosomes, gonads, and their interaction shape responses to demyelination. We found that sex-biased oligodendrocyte and microglial responses are driven by interaction of sex chromosomes and gonads prior to myelin loss. Post demyelination, sex chromosomes mainly guide microglial responses, while gonadal composition influences oligodendrocyte signaling. Significantly, ablation of the X-linked gene Toll-like receptor 7 (Tlr7), which exhibited sex-biased expression during demyelination, abolished the sex-biased responses and protected against demyelination.

Both Nuclear and Membrane Estrogen Receptor Alpha Impact the Expression of Estrogen Receptors and Plasticity Markers in the Mouse Hypothalamus and Hippocampus.

Estrogens via estrogen receptor alpha (ERα) genomic and nongenomic signaling can influence plasticity processes in numerous brain regions. Using mice that express nuclear only ERα (NOER) or membrane only ERα (MOER), this study examined the effect of receptor compartmentalization on the paraventricular nucleus of the hypothalamus (PVN) and the hippocampus. The absence of nuclear and membrane ERα expression impacted females but not males in these two brain areas. In the PVN, quantitative immunohistochemistry showed that the absence of nuclear ERα increased nuclear ERß. Moreover, in the hippocampus CA1, immuno-electron microscopy revealed that the absence of either nuclear or membrane ERα decreased extranuclear ERα and pTrkB in synapses. In contrast, in the dentate gyrus, the absence of nuclear ERα increased pTrkB in synapses, whereas the absence of membrane ERα decreased pTrkB in axons. However, the absence of membrane only ERα decreased the sprouting of mossy fibers in CA3 as reflected by changes in zinc transporter immunolabeling. Altogether these findings support the idea that both membrane and nuclear ERα contribute overlapping and unique actions of estrogen that are tissue- and cellular-specific.

Sex Differences in Neurodegeneration: The Role of the Immune System in Humans.

Growing evidence supports significant involvement of immune dysfunction in the etiology of neurodegenerative diseases, several of which also display prominent sex differences across prevalence, pathology, and symptomology. In this review, we summarize evidence from human studies of established and recent findings of sex differences in multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and discuss how sex-specific central nervous system innate immune activity could contribute to downstream sex differences in these diseases. We examine human genomic and transcriptomics studies in each neurodegenerative disease through the lens of sex differences in the neuroimmune system and highlight the importance of stratifying sex in clinical and translational research studies. Finally, we discuss the limitations of the existing studies and outline recommendations for further advancing sex-based analyses to uncover novel disease mechanisms that could ultimately help treat both sexes.