The γ-secretase protein quartet, and its roles in brain development and Alzheimer's disease. Presenilin-1, nicastrin, APH-1 and PEN-2 form a functional γ-secretase complex, located in the plasma membrane and endoplasmic reticulum (ER) of neurons. The complex cleaves Notch (left) to generate a fragment (NICD) that moves to the nucleus and regulates the expression of genes involved in brain development and adult neuronal plasticity. The complex also helps in generating the amyloid β-peptide (Aβ; centre). This involves an initial cleavage of the amyloid precursor protein (APP) by an enzyme called BACE (or β-secretase). The γ-secretase then liberates Aβ, as well as an APP cytoplasmic fragment, which may move to the nucleus and regulate gene expression. Mutations in presenilin-1 that cause early-onset Alzheimer's disease enhance γ-secretase activity and Aβ production, and also perturb the ER calcium balance. Consequent neuronal degeneration may result from membrane-associated oxidative stress, induced by aggregating forms of Aβ (which create Aβ plaques), and by the perturbed calcium balance.

Reprinted by permission from Nature

Mattson, M. Nature. 422, 385-387 (2003)