Clinical Pharmacology & Biopharmaceutics
Open Access

Abstract

Alzheimer��?s Disease (AD) is one of the top public health challenges facing the Western world and developing countries due to ever-increasing population aging. Currently, there is no effective means to prevent or treat AD. Since 1998, there have been over 100 drug trials targeting specific AD pathogenic mechanisms, all of which have failed. AD is a complex disease involving multiple interrelating pathogenic mechanisms. We hypothesized that strategies to simultaneously target multiple pathogenic mechanisms may increase the likelihood of therapeutic success. Polyphenols are receiving increasing attention for their potential role in preventing the onset and/or progression of age dependent preclinical AD. We previously reported that select cocoa-derived polyphenols can reduce AD-type neuropathology and attenuate cognitive decline in various mouse models of AD. More recently, we identified polyphenols metabolites, either individually or in combination, that can selectively influence specific AD pathologic features for translational therapeutic strategies. In particular, we identified 16 brain-bioavailable bioactive polyphenol metabolites with drug-like properties and in vivo safety profiles that can beneficially influence major AD-related neurodegenerative mechanisms following treatments with polyphenols. Following brain isolation and structural identification of these metabolites, we are currently investigating their brain target engagement and mechanisms of action in mouse models of AD genetically engineered to develop AD-like synaptic degeneration, blood-brain barrier damage, and tau pathology. Moreover, new preliminary clinical evidence supporting the clinical development of brain-bioavailable bioactive polyphenol precursors, capable of delivering bioactive metabolites for pre-symptomatic AD subjects to delay/prevent the onset AD dementia, will be discussed.

Biography

Email: giulio.pasinetti@mssm.edu