Now Tsai shows that excess p25 can also accelerate the production of amyloid-β and formation of plaques, thus linking the three major pathological signatures of AD—amyloid-β plaques, and neurofibrillary tangles—and neuronal death.

Tsai has raised mice that express p25 driven by a promoter that can be shut off by the antibiotic doxycycline. Removing this safety valve leads to overexpression of p25 in the brain. When Tsai allowed these animals to mature to adulthood and then removed the antibiotic from their diets, the results were profound. The mice developed all the hallmarks of AD, including elevation of the Aβ42 peptide that triggers the development of plaques. Since p25 accumulates in the brains of people with AD (see ARF related news story), these results suggest that cleavage of p35 may be a trigger for the disease. It is also worth noting that p25 has been shown to accumulate following stroke (see ARF related news story). Among the current hypotheses for how the pathology of Alzheimer’s begins is that hypoperfusion, or mini strokes, may be key (see ARF Live Discussion on vascular factors in AD).—Tom Fagan.