Alzheimer's, the new pathway from the scavenger protein that cleans neurons

The study started with a genetic screening of lab-grown human neurons using DNA 'scissors' based on CRISPR technology to map the internal systems that control tau accumulation within brain cells.

The aggregates that form as neurofibrillary tangles within nerve cells over time cause the death of neurons, leading to pathologies such as Alzheimer's, frontotemporal dementia or other diseases characterised by neurodegeneration.

'We wanted to understand why some neurons are vulnerable to tau accumulation while others are more resilient,' is the comment in a press note from Samelson University.

By systematically examining almost all genes in the human genome, we found both expected and totally unexpected pathways that control tau levels in neurons,' The researchers' analysis in particular assessed genes that could promote tau accumulation by deactivating individual genes to see how each influenced toxic tau aggregation.

And it revealed a protein complex, CRL5SOCS4, linked to the gene of the same name among more than 1,000 examined, which acts by binding chemical markers to tau, thus signalling the cellular recycling mechanism to destroy it.

It must be said that by examining the brain tissue of people with Alzheimer's disease, the researchers added another piece to the knowledge, finding that neurons with higher levels of CRL5SOCS4 components were more likely to survive, despite the accumulation of tau. This very observation opens up hope for the future.

The working hypothesis is that enhancing this natural purification pathway could form the basis of new therapies for neurodegenerative diseases.

As a further corollary to the study, a further toxicity-related aspect of the tau protein was also discovered, associated with the mitochondria, the cell's energy production powerhouses.

By altering these energy units, the cells involved began to produce specific tau fragments of around 25 kilodaltons, which closely correspond to a biomarker detected in the blood and spinal fluid of Alzheimer's patients, known as NTA-tau.

'This tau fragment appears to be generated when cells undergo oxidative stress, which is common in ageing and neurodegeneration,' is Samelson's comment. We found that this stress reduces the efficiency of the proteasome, the cellular protein recycling machine, causing it to improperly process tau'.

This aspect also appears to be of great importance in the development of future treatments: in the laboratory, this altered tau fragment has been shown to change the way tau proteins cluster, which could influence disease progression.

Not only that, if increased CRL5SOCS4 activity could help neurons clear tau more effectively, protecting mitochondria during periods of cellular stress could reduce the formation of harmful tau fragments.