Integrating spatial transcriptomics and single cell RNA-sequencing to mechanistically define bariatric surgery's impact on Alzheimer's Disease

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

PROJECT SUMMARY With a steadily increasing number of aged individuals, the number of people suffering from Alzheimer's disease (AD) is also increasing worldwide. Unfortunately, there have been only three FDA approved therapeutics for AD and these have failed to make major clinical impacts. The risk of AD is significantly increased by the development of obesity and type 2 diabetes (T2D) and studies recently performed show that glucose metabolism is disrupted in the brains and neurons of patients with AD with defects in glucose uptake and mitochondrial dysfunction. Interventions known to improve metabolic health like calorie or protein restriction, can extend lifespan while delaying age-related disease and slowing or preventing AD in animal models. However, dietary interventions like these are hard to sustain in the long term. Bariatric surgery (BS) is the most impactful therapy for obesity and metabolic disease. Sleeve gastrectomy (SG), the most performed bariatric surgery, has a profoundly positive impact on obesity, metabolic disease, and end organ health and can extend life by as much as 10 years. In humans, SG and other BS are associated with improved cognition, increased grey and white matter, and reduced circulating amyloid precursor protein. In preclinical studies, we have shown that SG mice are protected from metabolic disease in older age and that female mice prone to AD (3xTG) are protected from age-related frailty, cognitive decline, and AD-specific pathology. Others have shown that alternative forms of BS can similarly improve cognition, reduced Aβ plaque formation, tau phosphorylation, and microglial activation. Thus, there is growing evidence that SG may be able to treat or prevent AD but there has been a lack of preclinical studies aimed at understanding this phenomenon. Thus, there exists a major knowledge gap in our mechanistic understanding of how SG influences AD and if there are sex or strain differences in the response of AD to SG. This proposal, which is responsive to PAR-23-179, we will address these major outstanding questions. We will rigorously test the ability of SG to prevent metabolic disease, age-related frailty, and AD across sexes in two AD-prone mouse strains – APP/PS1(APP overexpressing) and hTau (tau overexpressing) - which will be preconditioned with western diet to induce obesity and T2D. We will perform deep metabolic and cognitive phenotyping and correlate these findings with traditional markers of AD pathology. Lastly, we will use a novel 10X Genomics platform to perform spatial transcriptomics and single nucleus RNAseq in SG and Sham brain specimen to help elucidate the mechanisms by which surgery impacts the pathogenesis of AD. The work proposed holds promise to simultaneously add to our mechanistic understanding of how altering metabolism can alter brain health and reveal novel targets for the future treatment of this devastating disease.