New Insights in the Amyloid-Beta Interaction with Mitochondria

Figure 2

APP processing in nondemented healthy individuals and AD patients. APP processing occurs by two pathways: a beta-secretase-based amyloidogenic and alpha-secretase-based nonamyloidogenic pathway. In the nonamyloidogenic pathway (left), cleavage occurs by alpha-secretase within the amyloid-beta domain and generates the large soluble N-terminal fragment (sAPPα) and a non-amyloidogenic C-terminal fragment of 83 amino acid residues (C83). Further cleavage of this C-terminal fragment by γ-secretase generates the nonamyloidogenic peptide (P3) and APP intracellular domain (ACID). These products are nontoxic. The non-amyloidogenic α-secretase pathway occurs in over 90% of humans, and these individuals generally do not develop dementia. In the amyloidogenic pathway (right), cleavage occurs by β-secretase at the beginning of the amyloid-beta domain and generates a soluble N-terminus fragment (sAPPβ) and amyloidogenic C-terminal fragment of 99 residues (C99). This C-terminal fragment is further cleaved by 𝛾-secretase and generates amyloid-beta. The amyloidogenic pathway occurs in approximately 10% of total humans, and these individuals might develop dementia and AD.