Presenilin U-turn

New data that turn the presenilin/γ-secretase hypothesis of Alzheimer's disease on its head do more than clear up the inconsistencies around the target that have confused the field for the last few years. As well as showing inhibition rather than activation of γ-secretase causes amyloid buildup in mouse brains, the data provide a salutory reminder that when studies produce the opposite of what's expected, it makes more sense to question the hypothesis than invoke new mechanisms to explain the results.

For over a decade, the AD field operated on the assumption that overactivity of γ-secretase was involved in disease pathology because inherited mutations in the presenilin genes PSEN1 and PSEN2 are associated with aggressive, early onset AD and increases in β-amyloid plaques. Presenilin is the catalytic subunit of γ-secretase, a transmembrane enzyme that cleaves APP to produce the Aβ40 and Aβ42 peptides found in the plaques...