Enhancing ?-secretase processing for Alzheimer’s disease—a view on SFRP1

Abstract

Amyloid ? (A?) peptides generated via sequential ?-and ?-secretase processing of the amyloid precursor protein (APP) are major etiopathological agents of Alzheimer’s disease (AD). However, an initial APP cleavage by an ?-secretase, such as the a disintegrin and metalloproteinase domain-containing protein ADAM10, precludes ?-secretase cleavage and leads to APP processing that does not produce A?. 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 A? 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 ?-secretase-effected APP processing in AD with a focus on SFRP1, and explore the contrasting perspectives arising from the recent findings. © 2020 by the author. Licensee MDPI, Basel, Switzerland.