2022 – CURE ALZHEIMER’S FUND GRANT RECIPIENT
Identifying the sex-specific roles of the gut microbiome-brain axis in a mouse model of amyloid beta amyloidosis
2022 – SAFADI PILOT GRANT RECIPIENT
The role of sex hormones and the gut microbiome in Alzheimer’s disease pathology
Dr. Piyali Saha
Postdoctoral Fellowship Support
Department of Neurobiology
In collaboration with the Department of Medicine and the Department of Obsterics and Gynecology
Alzheimer’s Disease (AD) remains the most common form of dementia, affecting 50 million people worldwide. Recent studies from our laboratory have established that perturbations of the gut microbiome with antibiotics lead to an attenuation of amyloid beta deposition and alterations in the physiology of microglia, cells that are critical for amyloid beta clearance. Importantly, these findings are unique to male but not female mice. Genetic and epidemiological studies have documented that women are at higher risk for AD than men. Is estrogen an important hormone that drives these differences? Current studies in the lab aim to delineate the mechanism(s) by which circulating levels of estrogen influence amyloid beta deposition and neuroinflammation. Our investigations will provide important information pertaining to the role of female sex hormones in modulating pathogenesis in our mouse models- findings that we anticipate will offer new therapeutic targets that will alter the onset and/or progression of AD in women.
An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo
Zhang, X., Zhang, C.M., Prokopenko, D., Liang, Y., Zhen, S.Y., Weigle, I.Q., Han, W., Aryal, M., Tanzi, R.E., Sisodia, S.S.
Familial Alzheimer’s disease (FAD)–linked mutations in the APP gene occur either within the Aβ-coding region or immediately proximal and are located in exons 16 and 17, which encode Aβ peptides. We have identified an extremely rare, partially penetrant, single nucleotide variant (SNV), rs145081708, in APP that corresponds to a Ser198Pro substitution in exon 5. We now report that in stably transfected cells, expression of APP harboring the S198P mutation (APPS198P) leads to elevated production of Aβ peptides by an unconventional mechanism in which the folding and exit of APPS198P from the endoplasmic reticulum is accelerated. More importantly, coexpression of APP S198P and the FAD-linked PS1ΔE9 variant in the brains of male and female transgenic mice leads to elevated steady-state Aβ peptide levels and acceleration of Aβ deposition compared with age- and gender-matched mice expressing APP and PS1ΔE9. This is the first AD-linked mutation in APP present outside of exons 16 and 17 that enhances Aβ production and deposition.
