Therapeutic approaches to Alzheimer’s disease through stimulating of non-amyloidogenic processing of amyloid precursor protein

Y.-Q. Wang, D.-H. Qu, K. Wang

The Second Affiliated Hospital of Jilin University, Nanguan District, Changchun, Jilin, China. kewangm1@hotmail.com

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• Neurology

Amyloid beta (Aβ) plaques are pathological hallmarks of neurodegenerative Alzheimer’s disease (AD) that is predominantly characterized by clinical symptoms of dementia. Therapies targeting Aβ are essential for preventing and treating AD. This review focuses on the non-amyloidogenic pathways that prevent the generation of Aβ peptide and thereby plaque formation in AD. An a-secretase-dependent cleavage of Amyloid Precursor Protein (APP) precludes the amyloidogenic pathway of Aβ generation. This non-amyloidogenic a-secretase activation thereby secretes sAPPa with prominent neurotrophic and memory-enhancing properties. Several “A Disintegrin and Metalloprotease” (ADAM) proteins, specifically ADAM17, ADAM10 and ADAM9, comprise active members of this a-secretase family. It is conventionally accepted that whereas ADAM10 executes constitutive APP cleavage, ADAM17 and ADAM9 are dedicated towards the regulated processing. Therefore, promoting a-secretase activity offers thorough neuroprotection against AD, and emerges as a pertinent strategy in attenuating Aβ. We discuss signaling pathways, particularly those mediated by protein kinase C and phorbol esters, that enhance ADAM functioning and sAPPa release. We also elaborate upon the associated M1 and M3-muscarinic acetylcholine receptors, ERK-MAP kinase, tyrosine kinase and calcium signaling pathways. Clinical studies suggest that regulated hormone and cholesterol levels are essential for restricting neurodegeneration, and here we illustrate the role of estrogen and testosterone and that of cholesterol-attenuating statins in generating sAPPa. We also emphasize the need for novel ADAM activators that may be screened for targeting the interleukin-1-responsive mRNA 5’-untranslated region of APP. This review offers an in-depth insight into pathways, strategies and probable therapies restricting AD pathology via its non-amyloidogenic route.

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