Opposite changes in APP processing and human Aβ levels in rats carrying either a protective or a pathogenic APP mutation

Cleavage of APP by BACE1/β-secretase initiates the amyloidogenic cascade leading to Amyloid-β (Aβ) production. α-Secretase initiates the non-amyloidogenic pathway preventing Aβ production. Several mutations cause familial Alzheimer's disease (AD), while the Icelandic mutation near the BACE1-cle...

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Bibliographic Details
Published in:eLife 2020-02, Vol.9
Main Authors: Tambini, Marc D, Norris, Kelly A, D'Adamio, Luciano
Format: Article
Language:English
Subjects:
abeta
Aging
alzheimer disease
Alzheimer Disease - metabolism
Alzheimer's disease
Amyloid
Amyloid beta-Peptides - genetics
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - genetics
Amyloid beta-Protein Precursor - metabolism
Amyloidogenesis
Animals
APP
Cognitive ability
Dementia disorders
Enzyme-Linked Immunosorbent Assay
Female
Gene Dosage
Humans
Male
Metabolites
Mutation
Neurodegeneration
Neurodegenerative diseases
Neuroscience
Protein turnover
Rats
Rats, Transgenic
Reproducibility of Results
Rodents
Secretase
β-Site APP-cleaving enzyme 1
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Summary:Cleavage of APP by BACE1/β-secretase initiates the amyloidogenic cascade leading to Amyloid-β (Aβ) production. α-Secretase initiates the non-amyloidogenic pathway preventing Aβ production. Several mutations cause familial Alzheimer's disease (AD), while the Icelandic mutation near the BACE1-cleavage site protects from sporadic dementia, emphasizing APP's role in dementia pathogenesis. To study APP protective/pathogenic mechanisms, we generated knock-in rats carrying either the protective ( ) or the pathogenic Swedish mutation ( ), also located near the BACE1-cleavage site. α-Cleavage is favored over β-processing in rats. Consequently, non-amyloidogenic and amyloidogenic APP metabolites are increased and decreased, respectively. The reverse APP processing shift occurs in rats. These opposite effects on APP β/α-processing suggest that protection from and pathogenesis of dementia depend upon combinatorial and opposite alterations in APP metabolism rather than simply on Aβ levels. The Icelandic mutation also protects from aging-dependent cognitive decline, suggesting that similar mechanisms underlie physiological cognitive aging.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.52612