Abstract
This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer’s disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aβ production, Aβ clearance, and hyperphosphorylation of tau proteins. Aβ itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aβ is produced as an AMP in response to HSV-1 and other brain infections, leading to Aβ deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical trials treating HSV-1-infected MCI and AD patients with antiviral medication is discussed.
Highlights
Alzheimer’s disease (AD) is an inflammatory neurodegenerative disease characterized by progressive decline in cognitive abilities, behavioral abnormalities, and the loss of ability to function at work or in activities of daily living
The authors suggest that these findings, along with the shared peptide homology between Aβ and herpes simplex virus type 1 (HSV-1) envelope glycoprotein B (Cribbs et al, 2000), indicate that the Aβ effect on HSV-1 replication may involve the insertion of Aβ into the viral envelope, which prevents entry of the virus into the host cell (Bourgade et al, 2015)
The results indicate that HSV-1 reactivation occurs more often in the amnestic MCI (aMCI) group and suggest that HSV-1 reactivation contributes to development of aMCI (Kobayashi et al, 2013)
Summary
Alzheimer’s disease (AD) is an inflammatory neurodegenerative disease characterized by progressive decline in cognitive abilities, behavioral abnormalities, and the loss of ability to function at work or in activities of daily living. HSV-1 infection of human neuroblastoma cells and rat cortical neurons activates the host cell amyoidogenic pathway, resulting in multiple cleavages of AβPP with accumulation of intracellular and secreted extracellular Aβ1–42, Aβ1–40, and several additional neurotoxic Aβ-containing AβPP fragments. Proteins, DNA and RNA within neuronal cells is found in AD brains, and occurs early in the disease (Bonda et al, 2010; Zhao and Zhao, 2013; Scheff et al, 2016) This type of stress is associated with other aspects of AD-related pathophysiology as well, including mitochondrial dysfunction, accumulation of redox metals, dysregulation of calcium homeostasis, hyperphosphorylation of tau proteins, Aβ accumulation, synaptic dysfunction, neuroinflammation and neurodegeneration (MondragónRodríguez et al, 2013; Zhao and Zhao, 2013; Tönnies and Trushina, 2017). Neuronal apoptosis has been demonstrated in human HSE brain tissue and cultured human glioblastoma cells infected by HSV-1 (Athmanathan et al, 2001)
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