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Amyloid precursor protein isoforms differentially modulate amyloid‐beta metabolism
Author(s) -
Tan Tse Mien,
Lim Mei Li,
Chua Li Min,
Wong Boon Seng
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.823.13
Subject(s) - amyloid precursor protein , gene isoform , presenilin , p3 peptide , microbiology and biotechnology , biology , alzheimer's disease , amyloid precursor protein secretase , amyloid (mycology) , human brain , alpha secretase , alternative splicing , neuroscience , disease , gene , medicine , biochemistry , botany
Alzheimer's disease (AD) is the most common form of age‐related dementia. Accumulation of amyloid‐beta (Aβ) is a key neuropathological hallmark and Aβ is proteolytically derived from amyloid precursor protein (APP). There are three major APP splice forms in the human brain; APP 695 , APP 751 and APP 770 , but APP 695 is the predominant transcript. In AD‐afflicted human brain tissues, APP 751 and APP 770 expression were elevated. But it is unclear if APP isoforms have different propensity to generate Aβ. Increased expression of APP in Down syndrome (DS) is likely to account for the development of AD‐like neurological features including Aβ deposition in older DS individual. However, Aβ accumulation was not detected in trisomic DS animal model that also over‐express APP. The mechanisms underlying this discrepancy are unknown. To better understand this conundrum, we created an inducible neuronal APP‐knockout cell line that express human APP 695 , APP 751 or APP 770 . We observed that the longer APP isoforms is more prone to Aβ formation. Although APP expression is a major determinant to Aβ formation, their resultant accumulation is modulated by the expression and function of enzymes involved in Aβ metabolism.