Dissecting the role of microRNAs in the adipose tissue - brain crosstalk in early onset Alzheimer's Disease

Abstract

Early onset Alzheimer's disease (AD) affects individuals under 65 years old, which are often in a very productive phase and possess several family responsibilities leading to profound negative impacts in the patients and their families' life. Despite extensive research showing that genetic mutations in the amyloid precursor protein (APP) and presenilin 1 (PS1) genes are associated with early onset AD development, the underlying mechanisms are not yet fully understood and dissecting the early alterations of AD could lead to insights to improve prognosis by anticipating AD diagnosis and treatment. One of the early events in AD is the disruption of the blood-brain barrier (BBB) integrity which may allow the infiltration of harmful molecules into the central nervous system (CNS). Recent evidence suggests that the BBB impairment and peripheral metabolic dysfunctions, like obesity and diabetes, accelerate AD progression by compromising brain health. Therefore, understanding the mechanisms of periphery-to-brain communication is imperative in AD. One of the mediators of this communication are the microRNAs (miRNAs), small non-coding RNA molecules crucial for gene regulation and associated with various biological processes, including neurodegeneration. Seminal studies in which professor Mori have been involved demonstrated that the adipose tissue (AT) is a major source of extracellular miRNAs. Therefore, this project explores the innovative hypothesis that the altered transport of AT-produced miRNAs from the periphery to the brain is a key component of the early onset AD pathogenesis. For this, two work packages (WP) will be performed aiming to identify AT-derived miRNAs transported to the brain in response to early onset AD-related pathology (WP1); and investigate whether AT-derived miRNAs play a role in the early onset AD pathogenesis (WP2). In WP1, the profile of AT-derived miRNAs will be investigated in the hippocampus of a mouse model for the study of early onset AD (5xFAD transgenic mice) and the transference of miRNAs from AT to brain will be analyzed in mice lacking miRNA biogenesis in adipocytes. In WP2, the study of the early onset AD-related pathogenesis will be performed in animals lacking miRNA biogenesis in adipocytes by crossing them with the 5xFAD transgenic mice. In addition, the study of the effects induced by selected candidates of AT-derived miRNAs which reached the brain of these animals on AD pathophysiology is also proposed. By elucidating the role of miRNAs in the adipose tissue-brain crosstalk in early onset AD, this project could pave the way for innovative diagnostic and therapeutic strategies, potentially leveraging lifestyle interventions like exercise and dietary modifications to mitigate AD risk.