Role of Testosterone in Modulating Tau Pathogenesis in Females

PROJECT SUMMARY
Alzheimer’s disease (AD) and other tau-mediated neurodegenerative diseases are characterized by aggregation
and spread of pathological tau protein in the brain. Despite decades of research, effective interventions to these
diseases are still lacking. It is well-evidenced that women typically show greater tau pathology than men on the
AD trajectory; yet the reason for such sex differences is poorly understood. A better understanding of the
mechanisms underlying the greater tau deposition in women can benefit all by informing causal pathways of
disease and therapeutic targets and strategies that are optimal for each sex. Clinical evidence suggests that low
testosterone levels correlate with poorer cognitive function and greater risk for AD. In particular, a recent study in
the Alzheimer’s Disease Neuroimaging Initiative (ADNI) revealed that women with lower testosterone tend to have
higher levels of phosphorylated tau (p-tau) in cerebrospinal fluid (CSF), particularly among ApoE4 carriers. This
suggest that lower testosterone levels that typically characterize women may predispose them to pathological tau,
and contribute to sex differences observed in AD. To take these correlative findings to the necessary next step,
our overall objectives are to establish the causal relationship between testosterone and tau in females, to explore
the clinical applicability of testosterone therapy, and to elucidate the underlying molecular mechanisms. Given
testosterone’s anti-inflammatory actions and neuroprotective effects on AD-related outcomes, we hypothesize
that pharmacological induction of high testosterone protects against pathological tau accumulation and spread,
diminishes neuroinflammation and ameliorates cognitive deficits associated with tau pathogenesis, particularly
in ApoE4 females. Based on published preclinical studies on testosterone, we further hypothesize that the
protective effects of testosterone are linked to androgen receptor signaling in astrocytes and neurons, leading to
enhanced neuronal survival, synaptic integrity and reduces neuroinflammation. This project is a new direction in
our research program: In collaboration with experts on reproductive biology and gene expression, we will combine
our expertise in tau biology, sex hormones and transcriptomics to determine how testosterone modulates tau
pathogenesis in a sex-specific manner. We will: 1) Determine how increase of testosterone levels affects tau
pathogenesis in female tau transgenic mouse models with human ApoE4/E3 knock-in; 2) Elucidate the molecular
mechanism underlying the protective effects of testosterone in ApoE4 females by single nucleus RNA
sequencing, and determining the involvement of neuronal and astrocytic androgen receptor signaling. This
project aims to close critical gaps in our understanding of mechanisms underlying sex differences in tau
pathophysiology, and provide novel insights into the influence of androgen on molecular mechanisms central to
AD pathogenesis. Results from the proposed research will address NIA strategic goals: understand the
progression of Alzheimer’s (A), and identify potential therapeutic targets for the development of precision
medicine treatments for men and women (D).

Grant Number: 5R01AG078185-04
NIH Institute/Center: NIH
Principal Investigator: Xu Chen