Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10152-w
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Funding
- McGill University
- Fonds de Recherche du Quebec -Sante (FRQ-S)
- Pfizer Canada
- Levesque Foundation
- Douglas Hospital Research Centre
- Douglas Foundation
- Government of Canada
- Canada Fund for Innovation
- Brain@McGill
- Velux Stiftung
- Natural Sciences and Engineering Research Council of Canada
- Canadian Consortium on Neurodegeneration in Aging
- Canadian Institute of Health Research [MOP-133411]
- Studienstiftung des Deutschen Volkes
- Groupe de Recherche Axe sur la Structure des Proteines (GRASP, McGill University)
- DFG [SFB877-TPA3]
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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 beta peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of A beta 40 and A beta 42 into a common A beta 34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that A beta 34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, A beta 34 levels correlate with the overall A beta 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 beta 34/A beta 42 ratio, representing A beta degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that A beta 34 represents a marker of amyloid clearance and may be helpful for the characterization of A beta turnover in clinical samples.
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