Abstract
Alzheimer’s disease (AD) is characterised by the aggregation and deposition of amyloid-β (Aβ) peptides in the human brain. In age-related late-onset AD, deficient degradation and clearance, rather than enhanced production, of Aβ contributes to disease pathology. In the present study, we assessed the contribution of the two key Aβ-degrading zinc metalloproteases, insulin-degrading enzyme (IDE) and neprilysin (NEP), to Aβ degradation in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Using an Aβ fluorescence polarisation assay, inhibition of IDE but not of NEP, blocked the degradation of Aβ by human neurons. When the neurons were grown in a 3D extracellular matrix to visualise Aβ deposition, inhibition of IDE but not NEP, increased the number of Aβ deposits. The resulting Aβ deposits were stained with the conformation-dependent, anti-amyloid antibodies A11 and OC that recognise Aβ aggregates in the human AD brain. Inhibition of the Aβ-forming β-secretase prevented the formation of the IDE-inhibited Aβ deposits. These data indicate that inhibition of IDE in live human neurons grown in a 3D matrix increased the deposition of Aβ derived from the proteolytic cleavage of the amyloid precursor protein. This work has implications for strategies aimed at enhancing IDE activity to promote Aβ degradation in AD.
Original language | English |
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Article number | NS20230016 |
Number of pages | 12 |
Journal | Neuronal Signaling |
Volume | 7 |
Issue number | 4 |
Early online date | 25 Aug 2023 |
DOIs | |
Publication status | Published - Dec 2023 |
Bibliographical note
Funding:The authors gratefully acknowledge the financial support of the Dr Donald Dean Fund for Dementia Research, the Medical Research Council [grant numbers MR/N013255/1 and MR/M024997/1]; the Biotechnology and Biological Sciences Research Council [grant number BB/S016848/1] and the University of Manchester. The Bioimaging Facility microscopes used in this study were purchased with grants from BBSRC, Welcome and the University of Manchester Strategic Fund. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising.
Keywords
- Alzheimers disease
- amyloid beta
- insulin-degrading enzyme
- metalloproteases
- neprilysin
- neurons