The Hypothalamic-Limbic Axis as a Modulator of Alzheimer's Disease: An Experimental and Bioinformatics Approach

• Grant number: 25/13742-2
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2026
• End date: December 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Andre de Souza Mecawi
• Grantee: Andre de Souza Mecawi
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated research grant: 19/27581-0 - Control of vasopressin secretion in pregnancy and its implications in pathophysiology of Preeclampsia, AP.JP

Abstract

Alzheimer's disease (AD) is the leading cause of dementia in older adults and a growing global public health challenge. Its pathophysiology is complex, involving the accumulation of amyloid beta (A¿) and hyperphosphorylated tau, as well as a robust neuroinflammatory response that significantly contributes to progressive neurodegeneration. In our laboratory, we propose to investigate the impact of chronic dehydration as a stressor that exacerbates AD pathology. The central hypothesis postulates that osmotic stress resulting from water restriction promotes the chronic activation of magnocellular neurons (MCNs) located in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. These neurons are the primary source of production of the neuropeptide arginine vasopressin (AVP), a key hormone in the regulation of water homeostasis and blood pressure. Although the classical neuroendocrine function of MCNs is well established, robust neuroanatomical evidence demonstrates that these same neurons send direct axonal projections to several extra-hypothalamic areas, notably limbic regions such as the cerebral cortex and hippocampus. This direct anatomical connection provides a plausible substrate for hypothalamic MCN hyperactivity to directly influence the physiology and pathology of neurons and glial cells in brain regions crucial for memory and severely affected in AD. AVP signaling in these target regions occurs through its receptors, particularly the V1a (Avpr1a) and V1b (Avpr1b) subtypes, which are expressed in both neurons and cortical and hippocampal astrocytes. However, direct analysis of the hypothalamic transcriptome in AD models is still lacking, although projects in our laboratory ultimately aim to generate such data. Activity Plan 1 = Given this gap and opportunity, this project proposes an innovative, synergistic, and exclusively bioinformatics-based approach. We aim to identify and characterize a "transcriptomic signature" of AVP pathway activation in scRNA-seq data from the cortex and hippocampus, which are widely distributed in the literature. The detection and quantification of this signature in public data and, in the future, in data generated by the laboratory, will allow computationally testing the hypothesis that hyperactivity of the vasopressin system is correlated with the neuroinflammatory and pathological profile of AD in specific cell types. Activity Plan 2: Interestingly, in the hypothalamus, there is a nucleus called the supraoptic nucleus (SON), where the physiological characteristics of the disease are rarely found, proving resistant to AD. It has also been observed that there is an increase in the level of connectivity and activity of magnocellular neurons (MCNs) in aging. These neurons, located in the SON of the hypothalamus, are responsible for the synthesis and secretion of arginine vasopressin (AVP) in relation to the osmotic increase. When activated, MCNs secrete AVP into the neurohypophysis, which stimulates renal water reabsorption. Our hypothesis is that chronic dehydration, by imposing osmotic stress and chronically activating vasopressinergic MCNs, will exacerbate the expression profile of genes linked to neuroinflammation (such as C1QA, TREM2, and S100B) and amyloid pathology (APOE) in the mouse brain, with a possible sexual dimorphism effect, favoring greater severity in females. We will use APPSwe/PS1dE9 transgenic mice and their littermates without the APP/PS1- transgene, already subjected to a water restriction protocol from 4 months of age, as well as hydrated controls. After euthanasia, we will collect fresh cortex, hypothalamus and hippocampus to perform gene expression analyses using the PCR technique to verify the expression of genes associated with disease progression through water restriction. (AU)