Alzheimer’s disease is frequently associated with two proteins: amyloid and tau. Amyloid manifests as sticky clusters outside nerve cells, while tau appears as twisted formations within them.
Many regard phosphorylated tau, or p-tau, as a clear sign of damage. Yet, there’s another layer to this narrative.
Linking HSV-1 with Alzheimer’s
Researchers from the University of Pittsburgh have uncovered an unexpected link between Alzheimer’s, tau proteins, and the herpes simplex virus-1 (HSV-1), which is known for causing cold sores.
This study suggests a role for viral stress and offers a surprising perspective on tau’s behavior during the early stages of the disease.
“Our findings challenge the traditional view of tau as purely detrimental, indicating that it might actually serve as part of the brain’s immune defense in the beginning stages,” said Or Shemesh, Ph.D., a senior author and assistant professor at Pitt.
“These insights highlight the intricate relationship between infections, immune responses, and neurodegeneration, paving the way for potential new treatment targets.”
Cellular paths in the brain
The brain consists of “roads” formed by nerve cells, which transmit signals essential for learning and memory.
When viruses infiltrate the nervous system, these roads can become strained. HSV-1, for instance, can remain dormant in cells and later reactivate.
This new research from Pitt investigates whether p-tau might sometimes act as an initial response when HSV-1 reactivates, rather than simply serving as a marker of decline.
The team posed two interlinked questions:
Can traces of HSV-1 be found in the brains of Alzheimer’s patients? If they exist, how do they relate to tau and amyloid-beta, particularly in critical areas like the hippocampus and entorhinal cortex?
Searching for viral traces
To explore this, they employed various methods to detect signs of the virus. Metagenomic DNA sequencing combed through tissue for snippets of viral genetic material.
Mass spectrometry was used to identify protein “fingerprints” linked to the virus, flagging specific proteins for further analysis with traditional lab techniques.
To determine the locations of these signals within cells, the researchers utilized expansion pathology. This technique causes preserved brain tissue to swell significantly, making it easier to see crowded molecules.
By allowing antibodies, which act as molecular markers, to penetrate more easily, they obtained a clearer nanoscale view of the relationship between viral proteins, tau, and amyloid in the same brain slice.
HSV-1 signals in Alzheimer’s patients
Multiple methods combined to reveal that HSV-1 proteins were indeed found in Alzheimer’s brains, and their presence tended to increase with the disease’s progression.
One particular protein, ICP27, drew attention. It’s classified as an “immediate-early” protein produced as soon as the virus reactivates within a cell, indicating active viral processes rather than a mere remnant of past infection.
Interestingly, ICP27 wasn’t universally present. Early in the disease, it was more frequently found in neurons in regions severely affected by Alzheimer’s. Later on, its presence shifted toward microglia, the brain’s immune cells, hinting that as damage escalates, microglia engage more with viral elements.
When comparing maps, the areas rich in ICP27 closely aligned with regions high in phosphorylated tau, but this did not extend to amyloid-beta plaques, showing a clear distinction between the two.
“Mini-brains” in the lab
To investigate cause and effect, the team cultivated human brain organoids, which are simplified “mini-brains” made from stem cells. After infecting these models with HSV-1, they observed an increase in tau phosphorylation.
Antiviral treatments that reduced the virus’s activity also resulted in decreased tau phosphorylation. Reactivating the virus, however, caused tau phosphorylation levels to rise again.
They flipped the question; what effect does the virus have on tau? When they increased phosphorylated tau, levels of ICP27 decreased, and more neurons were able to survive the infection.
In cultures without the enhanced p-tau, about two-thirds of neurons perished following infection, but with increased phosphorylated tau, only a small fraction died.
When protection turns harmful
These results help bridge two seemingly contradictory viewpoints. Controlled phosphorylation of tau in early phases might actually assist neurons in surviving HSV-1 attacks.
However, if this protective response is triggered too frequently or lasts too long, it can lead to misfolding, clumping, and tangling, disrupting transport within neurons and leading to degeneration.
This study doesn’t claim that p-tau is entirely “beneficial.” Instead, it underscores the importance of context and timing. A protective reaction that enables cells to endure infections can become harmful if it shifts into a chronic state.
HSV-1, Alzheimer’s, and future study
The interplay of infections, aging, and genetics in Alzheimer’s is likely quite complex. This research reinforces the idea that viral infections like HSV-1 may play a role in Alzheimer’s without acting as a straightforward cause. It also suggests promising avenues for developing therapies.
Overall, the findings suggest that p-tau may provide short-term protection but can evolve into a harmful factor if this response is sustained, presenting new opportunities for treatments aiming to manage viral activity or adjust these cellular alarm signals.
While the specific mechanisms by which HSV-1 influences tau protein and contributes to Alzheimer’s are still being unraveled, Shemesh and the team plan to dive deeper into these processes in their upcoming research.
The complete study is accessible in the journal Cell Reports.
