Peri-menopause as a neurological transition state that triggers Alzheimer's disease onset and accelerates disease progression

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ABSTRACT Prevalence and rate of progression of Alzheimer’s disease are 2-3-fold higher in post-menopausal women respect to age-matched men. Aside from the established vulnerability, the molecular mechanisms underlying the increased risk of Alzheimer’s disease in women are largely unknown. Alzheimer’s has a long prodromal phase which coincides with the menopause transition in women (peri-menopause, age ~45-54 years). Peri-menopausal women show higher levels of Alzheimer’s disease brain pathology [amyloid b (Ab) plaques, neurofibrillary tangles, synaptic loss, and chronic inflammation] compared to pre-menopausal women and men. This suggests that mechanisms unique to peri-menopause increase the susceptibility to Alzheimer’s disease leading to earlier onset and faster progression of the disease. The goal of this proposal is to elucidate the effects of peri-menopause on Alzheimer’s disease pathology and cognitive decline, as well as to identify molecular pathways differentially expressed in peri- menopausal females compared to young females, males, and ovariectomized females (as a mean of comparison to previous published studies). We hypothesize that irregular estrogen cyclicity and estrogen- estrogen receptor interactions during peri-menopause, rather than only loss of estrogen during post- menopause, increase the susceptibility to Alzheimer’s by magnifying the pathology in vulnerable brain regions leading to faster development of cognitive deficits. We will use a novel mouse model of accelerated ovarian failure (AOF) which uniquely recapitulates human menopause including peri- and post-menopause (peri- and post-AOF respectively). Two specific aims will test this hypothesis in the hAPP-J20 (J20) mouse model of Alzheimer’s. Aim 1 will test the sub-hypothesis that irregular estrogen fluctuations at peri-AOF will accelerate cognitive deficits, synaptic loss, and recruitment of microglia and astrocytes in hippocampus and prefrontal cortex (PFC) of J20 mice compared to control mice. Aim 2 will test the sub-hypothesis that peri-AOF disrupts neuronal pathways involved in Ab metabolism resulting in increased deposition of Ab plaques in the hippocampus and PFC of our AD females compared to age- matched controls. We will use a unique combination of sophisticated imaging and genomic analysis including iDisco, which will allow the 3D quantification of whole brain Ab and glia activation, and translational ribosomal profiling (TRAP) for sequencing the pool of actively transcribed mRNA in neurons. Our research outcomes will provide novel insights into the influence of peri-menopause on molecular mechanisms central to Alzheimer’s disease pathogenesis. Our findings 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).