A?34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer's disease progression.

ABSTRACT: The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of A? peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of A?40 and A?42 into a common A?34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that A?34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, A?34 levels correlate with the overall A? clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer's disease), we further demonstrate that the A?34/A?42 ratio, representing A? degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that A?34 represents a marker of amyloid clearance and may be helpful for the characterization of A? turnover in clinical samples.

SUBMITTER: Liebsch F 

PROVIDER: S-EPMC6527709 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature