The influence of dehydration and role of magnocellular neurons of the hypothalamus in the development of Alzheimers desease

• Grant number: 24/04792-3
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2024
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Andre de Souza Mecawi
• Grantee: Marcos Yuji Shiroma Graziano
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The Alzheimer's disease (AD) is one of the main causes of dementia and death in the elderly population. Clinically, it is characterized by progressive cognitive deficits, mainly regarding memory. Its physiopathology is characterized by the deposition of amyloid plaques in the extracellular space of the central nervous system (CNS) and by the formation of Tau protein tangles in the cytoplasm of neurons. Despite the recent advancements, the environmental factors associated to the development and progression of this desease are still not well known. Post-mortem studies demonstrated that while most of the CNS of humans with AD had shown dense deposition of amyloid plaques, the supraoptic nucleus of the hypothalamus (SON) had not, appearing to be resistant to the physiopathological markers of AD. It has also been documented that the magnocellular neurons (MCNs) maintained, or even increased, their number, activity and connectivity. The MCNs, mainly found in the SON, are responsible for the synthesis and secretion of the neuropeptide arginine-vasopressin (AVP) in response to dehydration. In such condition, the MCNs are intensely activated and secrete the AVP as a hormone via the neurohypophysis, stimulating the renal reabsortion of water. However, the MCNs also send collateral projections to several regions of the CNS, such as cortex and hipoccampus, regions that are severely affected by the deposition of amyloid plaques in AD. The MCNs synthetize several other neuropeptides aside from AVP, such as oxytocin, dynorphin and galanin. Recent data based on single cell transcriptome analysis demonstrated that MCNs of rodents and primates, including humans, express high levels of the App gene, which encodes the precursor protein of the beta-amyloid. It was also demonstrated that the App gene also has its expression enhanced by dehydration as well as physiological aging in the SON of rats. Therefore, when put through dehydration, aged rats activate genic pathways associated with AD and neurodegeneration in the SON. We hypothesize that a life-long poor hydration leads to a higher MCNs activity, which in turn synthetize higher quantities of the amyloid precursor protein (APP) and deposit it in regions of the cortex and the hippocampus, leading to the formation of amyloid plaques, which set off and/or aggravate AD. Our objective is investigate the influence of the hyperactivity of MCNs induced by a hydric restriction protocol on AD. To achieve that, male and female mice model for AD (APP/PS1) and wild type (C57BL) will be put through a hydric restriction protocol starting at 4 months old until they are 11 m.o. Throughout this period, the animals will be evaluated in cognitive tests (Y-maze, object and social recognition) and metabolic/locomotor activity (calorimetry). The animals will be euthanized afterwards. Morphological and molecular evaluations will be carried out in their MCNs, cortex and hippocampus. Plasmatic biochemistry evaluations will also be carried out (AVP, copeptin and osmolarity). With the present research project we hope to contribute to a better comprehension of the physiopathology of AD and its molecular and cellular mechanisms (the role of MCNs); to a possible development of early markers for predisposition of its development/aggravation (copeptin); and to the development of non-pharmacological strategies for the prevention/retardation of its symptoms/treatment (assisted hydration protocols).