Molecular links between HSV-1 and APP
Alzheimer's disease (AD) is a devastating neurodegenerative condition that currently affects an estimated 6.5 million Americans and 55 million individuals worldwide, with projections indicating this number could soar to 139 million by 2050. AD is characterized by neuronal death, cognitive decline, neuroinflammation, hyperactive glia,synaptic disruption, neurofibrillary tangles, alternative amyloid protein precursor (APP) processing, amyloid-beta (Aβ) oligomerization, and senile plaques. Familial AD, linked to mutations in the APP, presenilin 1/2, and ApoE genes, accounts for only 1-5% of all cases (1) but the root causes of non-familial AD remain elusive. Intriguingly, some evidence suggests an infectious etiology, particularly involving herpes simplex virus type 1 (HSV-1), which is present in the brains of most AD patients. Establishing a causal link is challenging, as both healthy and AD- affected individuals harbor this latent virus. However, recent studies demonstrating that HSV-1 can recreate AD hallmarks in tissue culture and animal models strongly support this emerging concept. This proposal explores the exciting possibility that HSV-1 directly impacts AD through its glycoprotein M (gM) and its interaction with the APP processing modulator ITM2B (Bri2). We aim to characterize how HSV-1 gM alters the expression levels of Bri2 and APP, their binding, intracellular localization, processing, and Aβ oligomerization in tissue culture and mice. This work will elucidate direct molecular links between HSV-1 and AD, ultimately enabling the design of innovative therapies targeting these host-pathogen interactions .