Recent Perspective About the Amyloid Cascade Hypothesis and Stem Cell-Based Therapy in the Treatment of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative condition that is clinically characterized by impaired cognitive functions. The major morphologically observed lesion of AD encompasses the accumulation of extracellular amyloid aggregates (plaques) formed of amyloid-β (Aβ) protein and of intracellular neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein. According to the currently accepted amyloid cascade hypothesis, the major induction factor underlying the loss of cholinergic neurons in the cortex and hippocampus is the pathological accumulation of a smaller protein fragments known as amyloid-β which in turn is derived from a larger membrane protein called amyloid precursor protein (APP). Based on this hypothesis, several diagnostic and drug-based therapeutic interventions were suggested, mostly targeting amyloid-β and hyperphosphorylated Tau proteins. Several data have emerged that might indicate the inconsistency of the amyloid cascade hypothesis. Moreover, due to the purely palliative nature of AD drugs used so far, new stem cell-based therapy has been suggested as a promising potential therapeutic approach. Several cell sources have been used, such as embryonic stem cells, neural stem cells, mesenchymal stem cells, and induced pluripotent stem cells. While this suite of cell-based trials has shown promising results in preclinical paradigms, stumbling blocks still exist in the current treatment regimens. The present review highlights the recent perspective that argues against the long standing amyloid cascade hypothesis as well as the major efforts in the experimental application of stem cellbased therapies used as treatment options for AD, and discusses the major impediments against their successful translation into clinical.