Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic Aβ Peptides.

ABSTRACT: Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing. We generated nine point mutations in the APP gene, changing the charge and/or hydrophobicity of the amino-acids which were previously shown as part of the CBS. Most mutations triggered a reduction of amyloid-β peptides Aβ40 and Aβ42 secretion from transiently transfected HEK293T cells. Only the mutations at position 28 of Aβ in the APP sequence resulted in a concomitant significant increase in the production of shorter Aβ peptides. Mass spectrometry (MS) confirmed the predominance of Aβx-33 and Aβx-34 with the APP<

SUBMITTER: Hanbouch L 

PROVIDER: S-EPMC9525381 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature