Pathological activity of familial Alzheimer’s disease-associated mutant presenilin can be executed by six different γ-secretase complexes
Copyright policy )Pathological activity of familial Alzheimer’s disease-associated mutant presenilin can be executed by six different γ-secretase complexes
gamma-Secretase is a protease complex, which catalyzes the final of two subsequent cleavages of the beta-amyloid precursor protein (APP) to release the amyloid-beta peptide (Abeta) implicated in Alzheimer's disease (AD) pathogenesis. In human cells, six gamma-secretase complexes exist, which are composed of either presenilin (PS) 1 or 2, the catalytic subunit, nicastrin, PEN-2, and either APH-1a (as S or L splice variants) or its homolog APH-1b. It is not known whether and how different APH-1 species contribute to the pathogenic activity of gamma-secretase complexes with familial AD (FAD)-associated mutant PS. Here we show that all known gamma-secretase complexes are active in APP processing and that all combinations of APH-1 variants with either FAD mutant PS1 or PS2 support pathogenic Abeta(42) production. Since our data suggest that pathogenic gamma-secretase activity cannot be attributed to a discrete gamma-secretase complex, we propose that all gamma-secretase complexes have to be explored and evaluated for their potential as AD drug target.
Familal Alzheimer’s disease, Amyloid beta-Peptides, RNA Splicing, Neurosciences. Biological psychiatry. Neuropsychiatry, γ-secretase, Kidney, Presenilin, Peptide Fragments, Cell Line, Amyloid beta-Protein Precursor, APH-1, Alzheimer Disease, Multienzyme Complexes, Amyloid β-peptide, Presenilin-2, Presenilin-1, Humans, Amyloid Precursor Protein Secretases, RC321-571
Familal Alzheimer’s disease, Amyloid beta-Peptides, RNA Splicing, Neurosciences. Biological psychiatry. Neuropsychiatry, γ-secretase, Kidney, Presenilin, Peptide Fragments, Cell Line, Amyloid beta-Protein Precursor, APH-1, Alzheimer Disease, Multienzyme Complexes, Amyloid β-peptide, Presenilin-2, Presenilin-1, Humans, Amyloid Precursor Protein Secretases, RC321-571
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