Reduced Aβ secretion by human neurons under conditions of strongly increased BACE activity

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The initial step in the amyloidogenic cascade of amyloid precursor protein (APP) processing is catalyzed by beta-site APP-cleaving enzyme (BACE), and this protease has increased activities in affected areas of Alzheimer's disease brains. We hypothesized that altered APP processing, due to augmented BACE activity, would affect the actions of direct and indirect BACE inhibitors. We therefore compared postmitotic human neurons (LUHMES) with their BACE-overexpressing counterparts (BLUHMES). Although β-cleavage of APP was strongly increased in BLUHMES, they produced less full-length and truncated amyloid beta (Aβ) than LUHMES. Moreover, low concentrations of BACE inhibitors decreased cellular BACE activity as expected, but increased Aβ1-40 levels. Several other approaches to modulate BACE activity led to a similar, apparently paradoxical, behavior. For instance, reduction of intracellular acidification by bepridil increased Aβ production in parallel with decreased BACE activity. In contrast to BLUHMES, the respective control cells (LUHMES or BLUHMES with catalytically inactive BACE) showed conventional pharmacological responses. Other non-canonical neurochemical responses (so-called 'rebound effects') are well-documented for the Aβ pathway, especially for γ-secretase: a partial block of its activity leads to an increased Aβ secretion by some cell types. We therefore compared LUHMES and BLUHMES regarding rebound effects of γ-secretase inhibitors and found an Aβ rise in LUHMES but not in BLUHMES. Thus, different cellular factors are responsible for the γ-secretase- vs. BACE-related Aβ rebound. We conclude that increased BACE activity, possibly accompanied by an altered cellular localization pattern, can dramatically influence Aβ generation in human neurons and affect pharmacological responses to secretase inhibitors.

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570 Biowissenschaften, Biologie
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BACE, APP, γ-secretase, neuropharmacology, Alzheimer’s
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ISO 690SCHOLZ, Diana, Yana CHERNYSHOVA, Anna-Katharina ÜCKERT, Marcel LEIST, 2018. Reduced Aβ secretion by human neurons under conditions of strongly increased BACE activity. In: Journal of neurochemistry. 2018, 147(2), pp. 256-271. ISSN 0022-3042. eISSN 1471-4159. Available under: doi: 10.1111/jnc.14467
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@article{Scholz2018-10Reduc-42846,
  year={2018},
  doi={10.1111/jnc.14467},
  title={Reduced Aβ secretion by human neurons under conditions of strongly increased BACE activity},
  number={2},
  volume={147},
  issn={0022-3042},
  journal={Journal of neurochemistry},
  pages={256--271},
  author={Scholz, Diana and Chernyshova, Yana and Ückert, Anna-Katharina and Leist, Marcel}
}
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