Brain Infection with Herpes Virus May Accelerate Progression of Alzheimer's Disease
- There is growing evidence that amyloid-ß peptide (Aß) is not a functionless catabolic byproduct, but rather fights microbial infection
- Researchers at Mass General investigated the activities of Aß against neurotropic herpes viruses and found that Aß inhibited herpes simplex virus 1 (HSV1) infection in cell cultures
- 5XFAD transgenic mice, which express high levels of human Aß in the brain, did not develop encephalitis when infected with HSV1
- HSV1 infection rapidly and dramatically accelerated ß-amyloid deposition in the brains of 5XFAD transgenic mice
- This study lends support to the theory that Aß is an antimicrobial peptide, and better understanding of its normal function might advance the effort to prevent Alzheimer's disease
Amyloid-β peptide (Aβ) has long been considered a functionless byproduct of catabolism. Accordingly, β-amyloid deposition, the hallmark of Alzheimer's disease (AD), has been viewed as intrinsically pathological.
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Intriguingly, though, there is growing evidence that Aβ is actually an antimicrobial peptide that evolved to fight brain infection with influenza, bacteria, fungi and, most notably, herpes viruses. Herpes simplex virus 1 (HSV1) upregulates Aβ generation, and in autopsy studies of AD patients, HSV1 DNA has been observed inside β-amyloid deposits.
Researchers at Massachusetts General Hospital have developed what they call the antimicrobial protection hypothesis of AD. They propose that infection can overactivate the Aβ innate immune pathways that are normally protective. Ongoing Aβ deposition drives neuroinflammation, leading to neuropathology and widespread neuronal death.
Most recently, the research team has uncovered a mechanism by which the presence of herpes viruses may promote Aβ deposition and accelerate AD pathogenesis. The findings are reported in Neurhttps://www.ncbi.nlm.nih.gov/pubmed/30001512on by a team led by Rudolph E. Tanzi, PhD, vice-chair of the Mass General Neurology Department, and Robert D. Moir, PhD, assistant professor in Neurology at Mass General.
The researchers first tested Aβ-mediated antiviral activity in a mouse model of HSV1 encephalitis. They administered intracerebral injections of HSV1 to wild-type mice and to 5XFAD transgenic mice, which express high levels of human Aβ in the brain but do not exhibit β-amyloid deposits or neuroinflammation with aging. The transgenic mice survived significantly longer than their non-transgenic littermates, demonstrating that Aβ protects against HSV1 encephalitis.
In further experiments, the researchers observed that:
- Aβ oligomers inhibited HSV1 infection in cell cultures
- Aβ bound and agglutinated HSV1 and human herpes virus 6 in cell cultures, with herpesviridae envelope glycoproteins being the binding targets
- HSV1 infection seeded Aβ deposition in the brains of 5XFAD transgenic mice, and by three weeks after infection, the deposits resembled the β-amyloid plaques found in the brains of patients with AD
According to the researchers, there is mounting evidence that microbial infections have an etiologic role in AD. They stress, however, that these findings do not prove that herpes viruses cause AD. What their data suggest is a plausible mechanism for direct viral mediation of β-amyloid deposition.
A better understanding of the normal activities of Aβ is likely to help in the development of Alzheimer's disease therapies that aim to prevent pathological Aβ accumulation.
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