Activation of the α-Secretase Processing of AβPP as a Therapeutic Approach in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is by far the main cause of dementia in the aged population. Because the amyloid-β peptide (Aβ) is the main component of senile plaques that develop in the brain of affected patients, numerous studies aimed at preventing its production or aggregation were conducted during the past 25 years. The inhibition of Aβ production via pharmacological inhibition of β- and γ-secretases is, with vaccination, one of the two main current challenges aimed at curing AD. However, the fact that there exist numerous substrates of these two activities renders this approach problematic since treatments with β- or γ-secretase inhibitors can cause deleterious effects. An alternative to the inhibition of the amyloidogenic enzymes would be to activate the α-secretase processing of AβPP. This cleavage is performed by two members of the disintegrin family of metalloproteases (ADAM10 and ADAM17). It is noteworthy that this cleavage can be seen as doubly beneficial regarding AD since it both occurs in the middle of the Aβ sequence and triggers the release of the neuroprotective sAβPPα product. However, similarly to β- and γ-secretases, ADAM10 and ADAM17 are responsible for the cleavage of a large number of proteins, the processing of some of them being tightly associated with important physiological functions but also with severe pathologies. This review focuses on our current knowledge of the various natural or synthetic compounds able to trigger α-secretase activities and on the possible ways to circumvent the deleterious side effects that would result from their broad activation.