Alzheimer's covertly linked to Herpes Simplex virus

The possibility that Alzheimer’s disease diagnosis is associated with viruses, bacteria, fungi, and parasites has been postulated over the past three decades.

By BEN EDIDIN

Researchers from the School of Pharmacy at the Hebrew University of Jerusalem have discovered a surprising correlation between Alzheimer‘s disease and the presence of Herpes Simplex Virus-1 (HSV-1). Their study, “Anti-Herpetic Tau Preserves Neurons vis the cGAS-STING-TBK1 Pathway in Alzheimer’s Disease,” was published in the peer-reviewed journal Cell Reports in early January.Alzheimer’s disease diagnosis depends on Neurofibrillary tangles, which are made predominantly of the proteins, extracellular β-amyloid (Aβ), and intracellular hyperphosphorylated tau (p-tau). The causes of these pathologies remained largely undiscovered.The possibility that Alzheimer’s disease diagnosis is associated with viruses, bacteria, fungi, and parasites has been postulated over the past three decades. Pathogens such as Aβ accumulation and tau phosphorylation have been considered potential triggers of neuropathological events in the brains of Alzheimer’s disease patients. Yet, the actual role of pathogens in activating the inflammatory processes that lead to Alzheimer’s diagnosis remains largely uncharted territory.

Growing evidence points to a possible connection between Alzheimer’s disease pathologies and infectious agents, with HSV-1 being a leading candidate. To prove the link between HSV-1 and Alzheimer’s disease, the researchers attempted to detect HSV-1 proteins in Alzheimer’s patient’s brains.

Neurons infected with herpes simplex virus 1 (credit: DR. FRED MURPHY/SYLVIA WHITFIELD/USCDCP/PIXNIO/COURTESY)

Results of the study

This study detected HSV-1 DNA and proteins in human brain samples through metagenomics, mass spectrometry, western blotting, and decrowding expansion pathology. These advanced techniques helped the research team identify 19 proteins associated with HSV-1 in the brains of Alzheimer’s patients. HSV-1 proteins were detected in all stages of the disease.

A significant discovery was the increased activity of a herpesvirus protein called ICP27, which became more prominent as the disease grew more severe.

In the hippocampus, a brain structure in the temporal lobe that plays a major role in learning and memory, the area occupied by ICP27 doubled from mild to advanced Alzheimer’s disease characterization. It tripled from no Alzheimer’s disease to advanced Alzheimer’s disease.

In the entorhinal cortex, a part of the medial temporal lobe that functions with memory, navigation, and the perception of time, the area occupied by ICP27 doubled among patients with no Alzheimer’s disease to mild/advanced Alzheimer’s disease.

This discovery strengthens the growing evidence that infections like HSV-1 might contribute to the development and progression of the disease.

ICP27 protein was found to occupy the same space as tau. The researchers hypothesized that HSV-1 infection leads to tau phosphorylation and contributes to the changes over time seen in Alzheimer’s.

The research team experimented with human brain organoids to further observe the colocalization of tau with HSV-1 proteins. These experiments revealed that HSV-1 can amplify tau modifications in specific locations linked to Alzheimer’s.

Remarkably, these modifications seem to work as neuron preservers, reducing the amount of virus and neuronal death. However, as the disease progresses, these same processes may contribute to the brain damage associated with Alzheimer’s disease.

Lead researcher Dr. Or Shemesh stated, “Our research shows how HSV-1 interacts with the brain and influences the pathologies of Alzheimer’s disease. Early on, the changes in tau may protect brain cells by limiting the virus, but as the disease advances, these same changes could lead to more harm and accelerate neurodegeneration.

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