Friday, May 16, 2025
5/16/2025
A TIMEM252-dependent Microvascular Endophenotype in Alzheimer’s Disease - Cerebrovascular dysfunction and blood-brain barrier (BBB) impairment are very common in neurological disorders, including age-related Alzheimer’s disease and related Dementia (AD/ADRD), head injuries including traumatic brain injury (TBI) and stroke. Microvascular injury and BBB breakdown often result in a cascade of events including extravasation of plasma proteins that are toxic to neuronal cells, parenchymal edema, hypoxia, metabolic stress including endoplasmic reticulum (ER) dysfunction, accumulation of metabolic wastes, activation of microglial and astrocytes, and eventually neuronal dysfunctions. Our central hypothesis is microvascular injury among different pathological conditions such as aging and AD can be attributed to an intrinsic molecular driver on BBB dysfunctions, which ultimately influence neuropathology and the development of cognitive impairment. Based on our preliminary data from comprehensive bioinformatic analysis and validations in multiple models of neurological disorders, we hypothesize that specific TMEM252 upregulation in BBB is a common molecular signature for microvascular injury. Mechanistically, TMEM252 may drive the microvascular injury endophenotype by inducing ER-dependent BBB dysfunctions. Hence, we propose to determine whether TMEM252 upregulation is a key event of microvascular injury and a common mechanism in aging and AD. More specifically, we will first provide a mechanistically understand TMEM252 functions in BBB (AIM 1), then understand the role of TMEM252 in age- and AD-associated microvascular injury using TMEM252-deficient mice (AIM 2), and finally examine the potential of targeting TMEM252 as an intervention for microvascular injury and BBB dysfunction in vivo (AIM 3). By phenotypically characterizing Tmem252 deficient model and its cross with Tg2576 model at multiple physiological levels, we hope to define a TMEM252-dependent link to vascular dysfunctions in aging and AD. As this molecular signature of microvascular injury was based on scRNA-seq analysis of multiple datasets obtained in TBI and aging mice, and cross-examined in human and mouse aging and AD samples, we expect that the propose project will provide very unique information regarding the common microvascular injury endophenotype across many neurological conditions. The data to be gathered from this study will expand our understanding of microvascular injury, as well as capture the nuance of the vascular changes between normal aging and AD. The successful completion of this study will provide new insights into the role of ER dysfunctions in microvascular injury, and novel molecular target for potential therapeutic intervention of microvascular injury in aging, AD and beyond.
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