HERPES SIMPLEX VIRUS-1 (HSV-1) AND ALZHEIMER'S DISEASE

Several epidemiological and experimental evidence suggested potential links between HSV-1 and Alzheimer's disease (AD), a neurodegenerative disorder characterized by a progressive decline in cognitive function and the accumulation in the brain of amyloid-? peptides (A?s), hyperphosphorylated forms of tau protein (pTau), that aggregate in neurofibrillary tangles, high levels of oxidative stress markers and neuroinflammation. However, these links have been considered merely associative throughout neuroscientists so far, since a causal relationship between HSV-1 and this disorder has yet to be definitely proved. Recently, an impressive analysis of postmortem brains points out herpes viruses as key agents in accelerating brains towards AD (Readhead et al, 2018), and another excellent study revealed how HSV-1 could speed up A? deposition as well as related amyloid plaque accumulation (Ezzat et al, 2019). Other authors highlighted the anti-microbic property of A?s, providing in vivo evidence on the capability of A? fibrils to entrap and neutralize herpesviruses (Eimer et al, 2018). Thus, some authors proposed that AD may result from an aberrant brain innate response to pathogen invasion, especially for HSV-1. Indeed, this peculiar virus can establish a life-long infection in humans, characterized by multiple reactivations that may also involve the brain. In this line, we recently provided novel evidence that multiple HSV-1 reactivations trigger in mouse brain accumulation of A?s, pTau, neuroinflammation, and oxidative damages, that are paralleled by increasing cognitive decline (De Chiara et al 2019). We then investigated how the virus may promote its spreading among neurons as well as the propagation of some virus-induced AD hallmarks, demonstrating that HSV-1 preserve the function of CRMP2, a protein involved in microtubule stabilization, to move inside neurons, and exploits extracellular vesicles (EVs) to infect and damage neighbor cells. We also explored the virus capability to affect neuron physiology, by altering the epigenetic mechanisms, demonstrating that it can accelerate the normal brain aging. Altogether, our findings support the view that multiple HSV-1 reactivations, causing mild but repeated viral spreading and replication in the central nervous system, maybe a risk factor for AD.