The g-secretase protein quartet, and its roles in brain development and Alzheimer's disease. Presenilin-1, nicastrin, APH-1 and PEN-2 form a functional g-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 b-peptide (Ab; centre). This involves an initial cleavage of the amyloid precursor protein (APP) by an enzyme called BACE (or b-secretase). The g-secretase then liberates Ab, 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 g-secretase activity and Ab production, and also perturb the ER calcium balance. Consequent neuronal degeneration may result from membrane-associated oxidative stress, induced by aggregating forms of Ab (which create Ab plaques), and by the perturbed calcium balance.
Reprinted by permission from Nature
Mattson, M. Nature. 422, 385-387 (2003)