Amyloid precursor protein isoforms differentially modulate amyloid‐beta metabolism

Abstract

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; APP695, APP751 and APP770, but APP695 is the predominant transcript. In AD‐afflicted human brain tissues, APP751 and APP770 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 APP695, APP751 or APP770. 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.