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Open AccessCommentary

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

by Bor Luen Tang 1,2
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore
Brain Sci. 2020, 10(2), 122;
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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