Pilot project: Neurovascular Aging Phenotypes of Alzheimer's Disease and Progeria: Focus on Inflammation and Blood Brain Barrier.

Ocean State Research Institute, Inc., Providence RI

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT Alzheimer?s disease (AD) is an age associated neurodegenerative disease characterized by gradual decline of memory, reasoning and judgement leading to mortality. Age is the major risk factor of AD followed by familial and sporadic inheritance. Beta (?) or ? secretase inhibitors slowdown the progression of the disease, but there no disease modifying therapies available for AD. Hutchinson-Gilford Progeria Syndrome (HGPS) is a unique accelerated aging genetic disease. Individuals with HGPS appear old and die of aging related cardiovascular diseases. However, unlike what is observed in AD, the cognitive functions of subjects with HGPS remain intact. The molecular mechanisms that protect the HGPS affected individuals from developing amyloid ? plaques characteristic of AD and memory loss are unknown. Microglial (MG) cells play a pivotal role in neuroinflammation. MG cells exhibit plasticity and can adopt neuroprotective or neurotoxic roles. Recent evidence suggest that MG cells mediate production of abnormally high levels of IL-1? and TNF? that are detected in AD brain. TNF? and IL- 1? can activate the cytokine receptors on the endothelial cells of the blood brain barrier (BBB) causing increased permeability of BBB. Our preliminary data suggests enrichment of pathways associated with cell surface interactions at the vascular wall, interleukin signaling, cell junction organization, chemokine signaling and Vascular Endothelial Growth Factor A (VEGFA)-VEGFR2 signaling. However, it is unclear if the neuronal resilience seen in HGPS is associated with MG derived cytokines and blood brain barrier functions. The main goal of the study is to investigate the neuronal resilience in HGPS versus the neuronal toxicity in AD. We will employ hiPSC cells from subjects with AD, HGPS,or age matched donors differentiated into MG cells to characterize the activated glial cell secretome and its effects on brain endothelial cell permeability. we hypothesize that AD neuronal risk and HGPS neuronal resilience is determined by the MG secretome and paracrine regulation of BBB endothelial cell permeability. The activated MG secretome (biased andunbiased) will be compared between normal, HGPS and AD to determine the AD risk. Understanding the factors conferring neuronal resilience to aging related factors in HGPS may offer novel therapeutic approaches for AD.