Abstract
Current data strongly suggest herpes simplex virus type 1 (HSV-1) infection in the brain as a contributing factor to Alzheimer’s disease (AD). The consequences of HSV-1 brain infection are multilateral, not only are neurons and glial cells damaged, but modifications also occur in their environment, preventing the transmission of signals and fulfillment of homeostatic and immune functions, which can greatly contribute to the development of disease. In this review, we discuss the pathological alterations in the central nervous system (CNS) cells that occur, following HSV-1 infection. We describe the changes in neurons, astrocytes, microglia, and oligodendrocytes related to the production of inflammatory factors, transition of glial cells into a reactive state, oxidative damage, Aβ secretion, tau hyperphosphorylation, apoptosis, and autophagy. Further, HSV-1 infection can affect processes observed during brain aging, and advanced age favors HSV-1 reactivation as well as the entry of the virus into the brain. The host activates pattern recognition receptors (PRRs) for an effective antiviral response during HSV-1 brain infection, which primarily engages type I interferons (IFNs). Future studies regarding the influence of innate immune deficits on AD development, as well as supporting the neuroprotective properties of glial cells, would reveal valuable information on how to harness cytotoxic inflammatory milieu to counter AD initiation and progression.
Highlights
Astrocytes, act in the opposite manner, by phagocyting and breaking down Aβ. The gravity of this feature is evidenced by the pharmacological ablation of astrocytes in organotypic brain culture slices (OBCSs) from 5XFAD mice, that entailed an increase in Aβ levels, reduced Aβ degradation, as well as reduced the density and size of hippocampal dendritic spines [164], following the ablation of the astrocytic proliferation in APP23/glial fibrillary protein (GFAP)-TK transgenic mice, which exacerbated the disease pathology in the mouse model of Alzheimer’s disease (AD) [165]
The available evidence of herpes simplex virus type 1 (HSV-1) presence in the brains of AD patients is not sufficient to confirm an inevitable role of the virus on its own in AD, because HSV-1 resides in the brains of healthy people [1], the discussed data corroborate that the presence of HSV-1 in the brain can be one of the factors initiating the formation of Aβ plaques, as well as one of the significant contributions leading to the onset of AD
On the second day of HSV-1 infection in mice, focal moderate cortical necrosis and myelin swelling were present in the brain, while from 7–10 days p.i., neuronal degeneration and deficits appeared in severely necrotic areas, and astrocyte/oligodendrocyte nuclei were substituted by karryorhectic figures indicating cell death [112]
Summary
During HSV-1 infection, neurons and glial cells produce many inflammatory mediators [66], and the rapid development of inflammation following CNS infection suggests that glial cells play a pivotal role in the initiation and progression of encephalitis. Viral DNA, but no HSV antigens, were found in the patient’s brain ten years after acute onset of HSE [19], indicating that following HSE, HSV-1 can establish latency in the TG and in the CNS cells, and constitute an ember for future brain infections as well as recurrent HSE. Such a possibility was proposed by Olsson et al [98]. During studies on neurodegenerative diseases, increasing attention is being directed towards glial cells triggering neuroinflammatory responses, as neuroinflammation is a composite process orchestrated primarily by various groups of glial cells in CNS, and peripheral immune cells [101]
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