The Alzheimer's Disease γ-Secretase Generates Higher 42:40 Ratios for ß-Amyloid Than for p3 Peptides.
Cell Rep
; 19(10): 1967-1976, 2017 06 06.
Article
em En
| MEDLINE
| ID: mdl-28591569
ABSTRACT
Alzheimer's disease is characterized by intracerebral deposition of ß-amyloid (Aß). While Aß40 is the most abundant form, neurotoxicity is mainly mediated by Aß42. Sequential cleavage of amyloid precursor protein (APP) by ß- and γ-secretases gives rise to full-length Aß (Aß1-x) and N-terminally truncated Aß' (Aß11-x) whereas cleavage by α- and γ-secretases leads to the shorter p3 peptides (Aß17-x). We uncovered significantly higher ratios of 42- versus 40-ending variants for Aß and Aß' than for p3 secreted by mouse neurons and human induced pluripotent stem cell (iPSC)-derived neurons or produced in a cell-free γ-secretase assay with recombinant APP-CTFs. The 4240 ratio was highest for Aß', followed by Aß and then p3. Mass spectrometry analysis of APP intracellular domains revealed differential processing of APP-C83, APP-C89, and APP-C99 by γ-secretase already at the ε-cleavage stage. This mechanistic insight could aid in developing substrate-targeted modulators of APP-C99 processing to specifically lower the Aß42Aß40 ratio without compromising γ-secretase function.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Peptídeos beta-Amiloides
/
Secretases da Proteína Precursora do Amiloide
/
Doença de Alzheimer
/
Neurônios
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article