AUTHOR=Bearer Elaine L. , Wu Chengbiao 

TITLE=Herpes Simplex Virus, Alzheimer’s Disease and a Possible Role for Rab GTPases

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 7 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2019.00134

DOI=10.3389/fcell.2019.00134

ISSN=2296-634X

ABSTRACT=Herpes simplex virus (HSV) is a common pathogen, infecting 85% of adults in the USA. After reaching the nucleus of the long-lived neuron, HSV may enter latency to persist throughout the life span. Re-activation of latent herpesviruses is associated with progressive cognitive impairment and Alzheimer's disease. As an enveloped DNA virus, HSV exploits cellular membrane systems for its life cycle, and thereby comes in contact with the Rab family of GTPases, master regulators of intracellular membrane dynamics. Knock-down and overexpression of specific Rabs (1, 5, 6, 11, 27a and 43) reduce HSV production.  Disheveled membrane compartments could lead to Alzheimer's disease because membrane sorting and trafficking are crucial for synaptic vesicles, neuronal survival and Abeta production. Amyloid precursor protein (APP), a transmembrane glycoprotein, is the parent of Abeta, the major component of senile plaques in Alzheimer's disease. Excess APP interferes with Rab5 endocytic trafficking in neurons. Here we show that purified PC12-cell endosomes transport both anterograde and retrograde when injected into the squid giant axon at rates similar to isolated HSV. Intracellular HSV co-fractionates with these endosomes, contains APP, Rab5 and TrkA, and displays a second membrane. HSV infected PC12 cells up-regulate APP expression. Whether interference with Rabs has a specific effect on HSV or indirectly affects membrane compartment dynamics co-opted by virus needs further study. Ultimately Rabs, their effectors or their membrane-binding partners may serve as handles to reduce the impact of viral re-activation on cognitive function, or even as more general-purpose anti-microbial therapies.