Enhancing α-secretase Processing for Alzheimer's Disease-A View on SFRP1.

Bor Luen Tang

doi:10.3390/brainsci10020122

Abstract

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.

Highlights

Alzheimer’s disease (AD) [1] is the most prevalent form of age-associated dementia [2]
AD etiology stems from amyloid β (Aβ) peptides [5] that are produced by two sequential amyloidogenic proteolytic cleavages of the amyloid precursor protein (APP), first by the β-site APP-cleaving enzyme 1 (BACE1) [6] followed by γ-secretase [7]
secreted-frizzled-related protein 1 (SFRP1) inhibits Wnt could be tumor suppressive via its inhibition of ADAM10′s sheddase activity, which liberates the signaling, which is important for neuronal function and synaptic integrity

Summary

Introduction

Alzheimer’s disease (AD) [1] is the most prevalent form of age-associated dementia [2]. SFRP1 inhibits Wnt could be tumor suppressive via its inhibition of ADAM10′s sheddase activity, which liberates the signaling, which is important for neuronal function and synaptic integrity. Symptom-attenuating effects ofhas experimental manipulations and essential forsecretase neurodevelopment and its aberrant activity been linked to several neurological drugs/compounds have been attributed to an enhancement of α-secretase-based APP processing, diseases other than AD [25,26]. As a pathophysiologically-relevant APP α-secretase [12], in neurons and the basal activity of ADAM10 in neurons is influenced by a myriad of regulators at many AD symptom-attenuating effects of experimental andpost-translationally drugs/compounds have the transcriptional and translational levels, as well as by manipulations modulations occurring (reviewed in [34,36]). I shall discuss SFRP10 s role in AD as deciphered by the authors, its potential as a target for AD therapy, and importantly, the reservations associated with the promises

Multiple Ways of Modulating α-secretase-Based APP Processing

Secreted-Frizzled-Related Protein 1 and Alzheimer’s Disease

Epilogue