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Open AccessCommentary

Enhancing α-secretase Processing for Alzheimer’s Disease—A View on SFRP1

by Bor Luen Tang 1,2
1
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore
2
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore
Brain Sci. 2020, 10(2), 122; https://doi.org/10.3390/brainsci10020122
Received: 10 February 2020 / Revised: 19 February 2020 / Accepted: 20 February 2020 / Published: 22 February 2020
(This article belongs to the Special Issue Neuropathology of Alzheimer’s Disease)
Amyloid β (Aβ) peptides generated via sequential β- and γ-secretase processing of the amyloid precursor protein (APP) are major etiopathological agents of Alzheimer’s disease (AD). However, an initial APP cleavage by an α-secretase, such as the a disintegrin and metalloproteinase domain-containing protein ADAM10, precludes β-secretase cleavage and leads to APP processing that does not produce Aβ. The latter appears to underlie the disease symptom-attenuating effects of a multitude of experimental therapeutics in AD animal models. Recent work has indicated that an endogenous inhibitor of ADAM10, secreted-frizzled-related protein 1 (SFRP1), is elevated in human AD brains and associated with amyloid plaques in mouse AD models. Importantly, genetic or functional attenuation of SFRP1 lowered Aβ accumulation and improved AD-related histopathological and neurological traits. Given SFRP1′s well-known activity in attenuating Wnt signaling, which is also commonly impaired in AD, SFRP1 appears to be a promising therapeutic target for AD. This idea, however, needs to be addressed with care because of cancer enhancement potentials resulting from a systemic loss of SFRP1 activity, as well as an upregulation of ADAM10 activity. In this focused review, I shall discuss α-secretase-effected APP processing in AD with a focus on SFRP1, and explore the contrasting perspectives arising from the recent findings. View Full-Text
Keywords: ADAM10; Alzheimer’s disease; amyloid β (Aβ); secreted-frizzled-related protein 1 (SFRP1) ADAM10; Alzheimer’s disease; amyloid β (Aβ); secreted-frizzled-related protein 1 (SFRP1)
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Tang, B.L. Enhancing α-secretase Processing for Alzheimer’s Disease—A View on SFRP1. Brain Sci. 2020, 10, 122.

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