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Sex and life experience shape locus coeruleus pretangle tau pathology

ABSTRACT: The locus coeruleus (LC) is the earliest site of tau pathology in Alzheimer’s disease (AD), yet how modifiable environmental factors influence its vulnerability, particularly in a sex-specific manner, remains unclear. Using a rat model expressing pseudophosphorylated human tau (htauE14) in the LC, we show that tau accumulation induces anxiety-like behavior, cognitive deficits, and tau spread, shaped by sex and life history. Early-life enrichment attenuated tau propagation, reduced neuroinflammation, and increased hippocampal BDNF expression, while late enrichment reduced anxiety and improved learning. In contrast, late-life stress exacerbated LC degeneration. Single-nucleus RNA sequencing revealed female-biased transcriptional dysregulation in hippocampal excitatory neurons and glia cells following htauE14 expression. Environmental exposures drove distinct cell type-specific transcriptomic signatures: early stress further disrupted mitochondrial and synaptic programs, whereas early enrichment conferred transcriptional stability. These findings position the LC as a sexually dimorphic and environmentally sensitive node of early AD vulnerability and highlight the preventive potential of early-life interventions.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE306235 | GEO | 2026/03/18

REPOSITORIES: GEO

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Project description:Microglia, the brain’s principal immune cells, have been implicated in the pathogenesis of Alzheimer’s disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared the transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic findings. There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally- and autosomally-encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

Project description:The locus coeruleus (LC) is a small noradrenergic nucleus in the dorsal pons that sends projections widely across the brain to regulate multiple functions including sleep, memory, arousal, and cognition. The LC has several unique cellular features including the presence of neuromelanin (NM) and its accumulation of a precursor to Alzheimer’s Disease (AD) pathology, soluble phospho-tau (pTau), in virtually all individuals by adulthood. NM increases in LC during early life, plateauing in middle age, and eventually dissipating, coinciding with LC neuron degeneration, a process which is observed in healthy aging but accelerated in AD. NM-sensitive neuroimaging predicts clinical severity and future progression of AD. While these findings suggest an etiologic role for the LC in AD, data describing the molecular landscape of the LC in middle age, preceding the clinical manifestation of sporadic AD, is lacking. Understanding the molecular state of the LC during this time period is critical to developing interventions that preserve this brain region and the cognitive functions it supports. Here, we performed Visium spatial transcriptomics on 85 tissue sections of human postmortem LC from a cohort of 33 middle-aged, neurotypical donors, balanced for epidemiologic AD risk factors including sex, African or European ancestry, and APOE genotypes (carriers of the E4/risk or E2/protective alleles). We find an unexpected male-bias in LC expression of cholesterol synthesis pathway genes, suggesting that intrinsic neuronal cholesterol synthesis may be protective against AD. Comparing across APOE genotypes, astrocytic gene expression differs in the immediate vicinity of LC neurons. Finally, we leverage histological images captured from the profiled tissue to associate gene expression to NM abundance, finding that APOE expression is associated with reduced NM content, and that NM-associated genes are enriched for aging-related pathways. These findings provide important information about how AD risk factors and NM content impact molecular correlates of resilience/susceptibility of the aging LC to degeneration. Data are freely available, including through visualization browsers to enable wide utilization of these tools for understanding LC biology in AD and other LC-related neurodegenerative disorders, including Parkinson’s disease.

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Sex and life experience shape locus coeruleus pretangle tau pathology

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