The Role of Amyloid-β in Neurodegeneration Inside Cells versus Outside Cells
Aggregates of misfolded amyloid-β outside cells are linked to the development of Alzheimer's disease. The failure of immunotherapies that clear those aggregates to achieve meaningful patient benefits indicates that the original form of the amyloid cascade hypothesis of Alzheimer's disease is not correct, however. It has been suggested of late that the aggregates are important because they represent a depletion of soluble amyloid-β, and thus they are the wrong target. An alternative view, described here, is that the prion-like spread of misfolded amyloid-β inside cells is the important issue, and the external aggregates only contribute to a worsening of that problem, rather than being the primary issue themselves.
An experimental study has revealed that the Alzheimer's protein amyloid-beta accumulates inside nerve cells, and that the misfolded protein may then spread from cell to cell via axons. This happens at an earlier stage than the formation of amyloid-beta plaques in the brain, something that is associated with the progression of Alzheimer's disease. The study in question builds on previous research based on amyloid-beta's prion-like properties. This means that the protein adopts a misfolded form that acts as a template for spreading in the brain, where it accumulates and develops plaques.
"The plaques of amyloid-beta outside the nerve cells have long been a target for treatment of Alzheimer's disease. But as treatments to remove plaque have not helped against dementia, we must develop and investigate other hypotheses in order to find other targets for treatment. Our results indicate that amyloid-beta is highly relevant, but that we must focus on misfolded amyloid-beta inside the nerve cells that arise far earlier than the visible plaques."
"The increased amyloid-beta caused by misfolded amyloid-beta inside cells can bring about a vicious circle of more and more amyloid-beta production. This could explain the enormous amounts of amyloid-beta that accumulate in the brain of Alzheimer's patients. However, our results indicate that many of amyloid-beta's damaging effects may be caused by what is happening within the cells, independent of plaques. This may explain why so many experimental treatments targeting plaques outside the nerve cells have failed and that we should focus our attention inwards."
Link: https://www.lunduniversity.lu.se/article/does-alzheimers-disease-start-inside-nerve-cells