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- W2897328127 abstract "β-secretase (BACE1) cleavage of amyloid precursor protein (APP) releases soluble APP-β (sAPPβ) and subsequent cleavage by γ-secretase produces Aβ. Therefore, while sAPPβ is a direct product of BACE1 cleavage of APP, Aβ is an indirect product. Nevertheless, BACE1 processing of APP is an obligate initial step in Aβ production, and sAPPβ is a surrogate marker of activity of BACE1, a high priority target for Alzheimer's disease (AD). Alternatively, APP cleavage by α-secretase precludes Aβ formation and produces soluble APP-α (sAPPα). Our previous data demonstrate an increase in cerebrospinal fluid (CSF) sAPPβ:sAPPα ratio in AD subjects versus controls, indicating a pathophysiological shift toward BACE1 processing of APP. Further, sAPPβ and Aβ concentrations are highly positively correlated in human CSF, suggesting BACE1 activity mediates both sAPPβ and Aβ differences among people. Therefore, we hypothesize that most AD patients overproduce Aβ due to increased BACE1 activity as measured by increased sAPPβ. To determine BACE1 and α-secretase activity in human CNS, human AD subjects (Amyloid+) and controls (Amyloid-) underwent 13C6-Leucine labeling and hourly CSF collection over 36 hours. Serially-sampled CSF underwent sequential immunoprecipitation to isolate sAPPβ and sAPPα, followed by tryptic digest. Resultant peptides were measured by liquid-chromatography/mass spectrometry to quantify kinetics and newly generated sAPPβ and sAPPα. Amyloid+ subjects have slower sAPPβ and sAPPα turnover rates than Amyloid-. The sAPPβ turnover rate is marginally slower than sAPPα, and this difference is accentuated in the setting of amyloid deposition. Newly generated sAPPβ, as well as the newly generated sAPPβ:sAPPα, were significantly elevated in Amyloid+. Importantly, these results strongly suggest increased processing of APP by BACE1 in subjects with brain amyloid deposition. By directly measuring kinetics and newly generated sAPPβ in vivo, we are determining if, and by how much, BACE1 activity is increased in AD. These results allow for characterization of AD subpopulations most likely to benefit from BACE1 inhibitors. Outcomes will elucidate human CNS APP physiology and AD pathophysiology and also prove useful for measuring pharmacodynamic effects of candidate therapeutics. Results of altered BACE1 activity in AD are critical for understanding AD pathophysiology and development of disease modifying therapeutics." @default.
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- W2897328127 date "2018-07-01" @default.
- W2897328127 modified "2023-10-16" @default.
- W2897328127 title "P1‐027: KINETIC BEHAVIOR OF NEWLY GENERATED BACE1‐CLEAVED APP IN THE HUMAN CENTRAL NERVOUS SYSTEM IN ALZHEIMER'S DISEASE" @default.
- W2897328127 doi "https://doi.org/10.1016/j.jalz.2018.06.028" @default.
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