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Inhibition of Amyloid Precursor Protein Processing Leads to Downregulation of Apoptotic Genes in Alzheimer's Disease Animal Models

Background and Methods: We previously reported the development of site-directed monoclonal antibodies able to inhibit the initiation of the amyloid precursor protein (APP) processing site, named ‘blocking β site 1' (BBS1). The beneficial effect of intracerebroventricular administration of these antibodies in the triple transgenic mouse model of Alzheimer's disease (AD) showed improvement in cognitive functions and reduction in tau and amyloid pathology. Amyloid-β may not be the only active component of AD neurotoxicity and may involve other proteolytic APP fragments such as the APP intracellular domain, proposed to work as a transcription factor involved in the regulation of p53 and glycogen synthase kinase 3β (GSK3β) as well as affecting several physiological processes contributing to AD pathology. Results: We show that inhibition of the β-secretase cleavage site via site-directed antibodies resulted in a major reduction in phosphorylated GSK3β levels, which is the active form of GSK3β, as well as in p53 levels. Conclusion: A therapy that is capable of reducing not only the direct hallmarks of AD but also the components that lead to neuronal apoptosis might have neuroprotective potential in AD treatment.