Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides

The Alzheimer amyloid precursor protein (APP) is cleaved by several proteases, the most studied, but still unidentified ones, are those involved in the release of a fragment of APP, the amyloidogenic β-protein Aβ. Proteolysis by γ-secretase is the last processing step resulting in release of Aβ. Cleavage occurs after residue 40 of Aβ [Aβ(1–40)], occasionally after residue 42 [Aβ(1–42)]. Even slightly increased amounts of this Aβ(1–42) might be sufficient to cause Alzheimer's disease (AD) (reviewed in ref. 1, 2). It is thus generally believed that inhibition of this enzyme could aid in prevention of AD. Unexpectedly we have identified in neurons the endoplasmic reticulum (ER) as the site for generation of Aβ(1–42) and the trans-Golgi network (TGN) as the site for Aβ(1–40) generation. It is interesting that intracellular generation of Aβ seemed to be unique to neurons, because we found that nonneuronal cells produced significant amounts of Aβ(1–40) and Aβ(1–42) only at the cell surface. The specific production of the critical Aβ isoform in the ER of neurons links this compartment with the generation of Aβ and explains why primarily ER localized (mutant) proteins such as the presenilins 3 could induce AD. We suggest that the earliest event taking place in AD might be the generation of Aβ(1–42) in the ER.