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
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
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