Herpes Simplex Virus Type-1 Infection Impairs Adult Hippocampal Neurogenesis via Amyloid-β Protein Accumulation

Abstract

We previously reported that Herpes simplex virus type-1 (HSV-1) infection of cultured neurons triggered intracellular accumulation of amyloid-β protein (Aβ) markedly impinging on neuronal functions. Here, we demonstrated that HSV-1 affects in vitro and in vivo adult hippocampal neurogenesis by reducing neural stem/progenitor cell (NSC) proliferation and their neuronal differentiation via intracellular Aβ accumulation. Specifically, cultured NSCs were more permissive for HSV-1 replication than mature neurons and, once infected, they exhibited reduced proliferation (assessed by 5′-bromo-deoxyuridine incorporation, Ki67 immunoreactivity, and Sox2 mRNA expression) and impaired neuronal differentiation in favor of glial phenotype (evaluated by immunoreactivity for the neuronal marker MAP2, the glial marker glial fibrillary astrocyte protein, and the expression of the proneuronal genes Mash1 and NeuroD1). Similarly, impaired adult neurogenesis was observed in the subgranular zone of hippocampal dentate gyrus of an in vivo model of recurrent HSV-1 infections, that we recently set up and characterized, with respect to mock-infected mice. The effects of HSV-1 on neurogenesis did not depend on cell death and were due to Aβ accumulation in infected NSCs. Indeed, they were: (a) reverted, in vitro, by the presence of either β/γ-secretase inhibitors preventing Aβ production or the specific 4G8 antibody counteracting the action of intracellular Aβ; (b) not detectable, in vivo, in HSV-1-infected amyloid precursor protein knockout mice, unable to produce and accumulate Aβ. Given the critical role played by adult neurogenesis in hippocampal-dependent memory and learning, our results suggest that multiple virus reactivations in the brain may contribute to Alzheimer's disease phenotype by also targeting NSCs. Stem Cells 2019;37:1467–1480

Multiple Herpes Simplex Virus-1 (HSV-1) Reactivations Induce Protein Oxidative Damage in Mouse Brain: Novel Mechanisms for Alzheimer’s Disease Progression

“…In addition, the virus was reported to trigger several neurotoxic pathways in neurons, including those related to the hyperphosphorylation/aggregation of the microtubule-associated tau protein [ 21 ] and synaptic dysfunction [ 22 ], the transcription of neurotoxic genes [ 23 ], and DNA damage [ 24 ]. Recently, by using a mouse model of recurrent HSV-1 infection, we showed the long-term dangerous effects of repeated HSV-1 replications in the brain (e.g., Aβ accumulation and deposition in plaques, tau hyperphosphorylation and aggregation, neuroinflammation), providing a first demonstration of the cause–effect relationship between HSV-1 reactivations and accumulation of AD molecular hallmarks, including cognitive deficits [ 25 ] and impaired adult neurogenesis [ 26 ]. Interestingly, HSV-1 life cycle is reported to induce an intracellular redox imbalance in host cells [ 27 , 28 ], and in vivo evidence demonstrated that this occurs also in the brain [ 29 ].…”

Patterns of Herpes Simplex Virus 1 Infection in Neural Progenitor Cells

“…This observation provides further evidence for the higher susceptibility of NPCs than of neurons to HSV-1. These data are particularly relevant in light of recent data that associate HSV-1 with Alzheimer's disease (31) and a recent report that showed accumulation of beta amyloid in neural stem cells harboring HSV-1 lytic infection (32).…”

The Use of Antimicrobial and Antiviral Drugs in Alzheimer’s Disease

“…HSV-1 has also been found to infect the hippocampus region at a greater rate; the same area found to have greater amounts of Aβ plaques in AD [ 81 ]. In vitro studies observed cells co-cultured with either HSV-1, HSV-2, P. gingivalis or B. burgdoferi to have increased intracellular concentrations of Aβ [ 80 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. Furthermore, HSV-1 has been associated with the inhibition of the non-amyloidogenic pathway of APP metabolism, and the increased expression of β-secretase.…”