Journal article

The Alzheimer's Disease gamma-Secretase Generates Higher 42:40 Ratios for beta-Amyloid Than for p3 Peptides

Alzheimer's disease is characterized by intracerebral deposition of beta-amyloid (A beta). While A beta(40) is the most abundant form, neurotoxicity is mainly mediated by A beta(42). Sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretases gives rise to full-length A beta (A beta(1-x)) and N-terminally truncated A beta' (A beta(11-x)) whereas cleavage by alpha- and gamma-secretases leads to the shorter p3 peptides (A beta(17-x)). We uncovered significantly higher ratios of 42-versus 40-ending variants for A beta and A beta' than for p3 secreted by mouse neurons and human induced pluripotent stem cell (iPSC)-derived neurons or produced in a cell-free gamma-secretase assay with recombinant APP-CTFs. The 42: 40 ratio was highest for A beta', followed by A beta and then p3. Mass spectrometry analysis of APP intracellular domains revealed differential processing of APP-C83, APP-C89, and APP-C99 by gamma-secretase already at the epsilon-cleavage stage. This mechanistic insight could aid in developing substrate- targeted modulators of APP-C99 processing to specifically lower the A beta(42): A beta(40) ratio without compromising g-secretase function.


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