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HSV-1 Induced Amyloid Beta-accumulation in NSCs Reduces Adult Neurogenesis

Review of “Herpes Simplex Virus Type‐1 Infection Impairs Adult Hippocampal Neurogenesis via Amyloid‐β Protein Accumulation” from STEM CELLS by Stuart P. Atkinson

Previous studies from the laboratories of Roberto Piacentini and Claudio Grassi (Università Cattolica del Sacro Cuore, Rome, Italy) established that the neurotropic Herpes simplex virus type‐1 (HSV‐1) induces the phosphorylation of amyloid precursor protein (APP) and subsequent cleavage by β‐ and γ‐secretases [1-4]. These modifications then promote the production of APP fragments, including the Alzheimer’s disease-associated amyloid‐β protein (Aβ), that can accumulate intracellularly and affect neuronal functions such as synaptic transmission. 

The team’s most recent study established that mice exposed to recurrent HSV‐1 reactivation without developing encephalitis exhibited Aβ accumulation in several brain areas, including the hippocampus, and display memory impairment [5]. Now, the team returns with a new STEM CELLS article in which they investigated the influence of HSV‐1 infection and Aβ accumulation on adult hippocampal neurogenesis by studying neural stem cells (NSCs) both in vitro and in vivo [6].

Li Puma et al. discovered higher replication of HSV‐1 following infection of undifferentiated Nestin-expressing NSCs isolated from the hippocampus of newborn mice when compared to mature neurons, with NSCs displaying a reduction in proliferation and the skewing of differentiation propensity away from neuronal and towards glial differentiation. Moving in vivo, the authors also established impaired adult neurogenesis in the subgranular zone of the hippocampal dentate gyrus in a mouse model of recurrent HSV‐1 infection with respect to mock‐infected mice. 

Interestingly, the study failed to find any relationship between cell death and lost neurogenesis; instead, the loss in the generation of new neurons came about due to Aβ accumulation in infected NSCs. Further evidence for the specific role of Aβ accumulation included the reversion of disease phenotype following the treatment of infected NSCs with β/γ‐secretase inhibitors that prevent Aβ production, or a specific 4G8 antibody that counteracts the activity of intracellular Aβ. Additionally, HSV‐1‐infected APP knockout mice did not produce or accumulate Aβ in the subgranular zone of the hippocampal dentate gyrus.

Overall, the authors provide a wealth of evidence that HSV‐1 infection of NSCs leads to reduced neurogenesis through the intracellular accumulation of Aβ, suggesting that this virus may significantly contribute to neurodegeneration and cognitive decline by acting upon NSCs of the subgranular zone of the hippocampal dentate gyrus. 

For more on NSCs, adult neurogenesis, and the potential role of viral infections in neurodegeneration, stay tuned to the Stem Cells Portal!

References

  1. De Chiara G, Marcocci ME, Civitelli L, et al., APP Processing Induced by Herpes Simplex Virus Type 1 (HSV-1) Yields Several APP Fragments in Human and Rat Neuronal Cells. PLOS ONE 2010;5:e13989.
  2. Piacentini R, Civitelli L, Ripoli C, et al., HSV-1 promotes Ca2+-mediated APP phosphorylation and Aβ accumulation in rat cortical neurons. Neurobiology of Aging 2011;32:2323.e13-2323.e26.
  3. Piacentini R, De Chiara G, Li Puma DD, et al., HSV-1 and Alzheimer’s disease: more than a hypothesis. Frontiers in Pharmacology 2014;5:97.
  4. Piacentini R, Li Puma DD, Ripoli C, et al., Herpes Simplex Virus type-1 infection induces synaptic dysfunction in cultured cortical neurons via GSK-3 activation and intraneuronal amyloid-β protein accumulation. Scientific Reports 2015;5:15444.
  5. De Chiara G, Piacentini R, Fabiani M, et al., Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice. PLOS Pathogens 2019;15:e1007617.
  6. Li Puma DD, Piacentini R, Leone L, et al., Herpes Simplex Virus Type-1 Infection Impairs Adult Hippocampal Neurogenesis via Amyloid-β Protein Accumulation. STEM CELLS 2019;37:1467-1480.