The ongoing search for effective treatments for Alzheimer’s disease has focused on aggregates of amyloid-β peptides, which are the hallmark of the disease. However, efforts to inhibit one of the proteins responsible for producing amyloid-β, called BACE1, have led to several failed Phase 3 clinical trials.

But researchers aren’t giving up hope. A study published in Science Translational Medicine on November 18 reveals how variants in a gene called GGA3—which are a known risk factor for developing Alzheimer’s—alter BACE1 movement through brain cells in culture and in mice. This causes the buildup of BACE1 protein and creates axonal damage similar to that seen in the pre-symptomatic stages of Alzheimer’s disease. This could mean BACE1 inhibitors still have promise as a treatment if used much earlier in the disease process.

“I think the core message from this paper is that this could be one additional primary pathogenic development that precedes amyloid plaques buildup,” says Henrik Zetterberg, a neuroscientist at the University of Gothenburg in Sweden who was not involved in the research. “What causes amyloid buildup? What are the primary pathogenic processes? That is pretty much unknown. We have the risk genes, of course, but this paper gives another very interesting piece of the puzzle of what might cause neurodysfunction in Alzheimer’s disease and could also cause amyloid buildup.”

Genetic studies have found that rare mutations in GGA3 increase the risk of Alzheimer’s disease. In previous research, the authors of the current study identified the role of the GGA3 protein in transporting BACE1 in non-neuronal cell lines. BACE1 is a protease responsible for cleaving the protein APP to produce the amyloid-β peptides that accumulate into plaques in Alzheimer’s. This new paper is the first demonstration of the consequences of GGA3 dysfunction on BACE1 in cultured neurons and mice.

More details can be found at : https://www.the-scientist.com/news-opinion/alzheimers-linked-mutation-causes-blockages-in-neurons-68175