New Insights into the Molecular Interplay between Human Herpesviruses and Alzheimer's Disease-A Narrative Review

Abstract

Human herpesviruses (HHVs) have been implicated as possible risk factors in Alzheimer's disease (AD) pathogenesis. Persistent lifelong HHVs infections may directly or indirectly contribute to the generation of AD hallmarks: amyloid beta (Aβ) plaques, neurofibrillary tangles composed of hyperphosphorylated tau proteins, and synaptic loss. The present review focuses on summarizing current knowledge on the molecular mechanistic links between HHVs and AD that include processes involved in Aβ accumulation, tau protein hyperphosphorylation, autophagy, oxidative stress, and neuroinflammation. A PubMed search was performed to collect all the available research data regarding the above mentioned mechanistic links between HHVs and AD pathology. The vast majority of research articles referred to the different pathways exploited by Herpes Simplex Virus 1 that could lead to AD pathology, while a few studies highlighted the emerging role of HHV 6, cytomegalovirus, and Epstein-Barr Virus. The elucidation of such potential links may guide the development of novel diagnostics and therapeutics to counter this devastating neurological disorder that until now remains incurable.

Keywords: Alzheimer’s disease viral hypothesis; amyloid beta (Aβ); human herpesviruses; neuroinflammation; tau protein.

Figure 1

Neurotropic human herpesviruses drive the generation of AD hallmarks directly via interactions with the viral surface (A), or indirectly by affecting different molecular mechanisms (B), such as mechanisms involved in Aβ deposition, tau protein hyperphosphorylation, autophagy, oxidative stress, and neuroinflammation. HVEM: Herpesvirus Entry Mediator, AICD: APP Intracellular Domain, gsk3β: glycogen synthase kinase 3β, UPR: Unfolded Protein Response, APP: Amyloid Precursor Protein, Aβ: Amyloid β, ER: Endoplasmic Reticulum, ROS: Reactive Oxygen Species.