A potential mechanism by which HHV-6A infection could promote Alzheimer’s Disease

HHV-6A was found to both enhance expression and inhibit degradation of amyloid precursor protein in vitro.

 Several groups have reported evidence linking HHV-6A to Alzheimer’s disease (Readhead 2018, Lin 2002, Carbone 2014, Westman 2017), whereas others have not (Bigley 2022, Allnutt 2020).  There is abundant evidence that three molecules are important in the pathogenesis of AD: amyloid-ß (Aß), phosphorylated tau, and APOE.  If HHV-6A can contribute to the pathogenesis of AD, it is plausible that it would do so by affecting one of these three molecules.

Amyloid precursor protein (APP) is the precursor to soluble Aß, a neurotoxic molecule, which then coalesces into plaques of Aß—a key feature of Alzheimer’s disease. Researchers at Nanjing Medical University in China investigated the impact of HHV-6A on the APP expression and degradation pathway.  They infected various cell lines including cord blood mononuclear cells, T cells, human glioma cells and mouse astrocytes with HHV-6A.

The HHV-6A U4 gene product was shown to be expressed in the early infection stage. The U4-expressing plasmid was introduced to cells with or without the APP gene. U4 increased expression of APP. U94 was also found to inhibit the overall ubiquitination of APP by binding to E3 ubiquitin ligase (Fig 1).

Fig 1 - Hypothetical model of U4 gene product inhibiting ubiquitination of APP.

This study reports a mechanism by which infection by HHV-6A of glial cells in the brain could both promote the expression and inhibit the degradation of APP, leading to the accumulation of plaques of Aß—a prominent feature of Alzheimer's disease.

This mechanism could contribute to a possible etiologic role for HHV-6A in AD. There is conflicting evidence of such an association—although there is stronger evidence that another herpesvirus, HSV-1, is associated with AD (Komaroff 2020). 

 Finally, many treatment studies directed at Aß in people with AD have had disappointing results. This could indicate that the deposition of Aß plaques in AD, while indisputably a central feature of the disease, is nevertheless an epiphenomenon that is not central to the pathology of AD. If that were the case, then the mechanistic role of HHV-6A in AD postulated by this study might not be relevant.

 Read the full article: Tang 2022