Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer's Disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-beta (A beta), a peptide of 40-42 amino acids. The conversion of A beta into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After A beta accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the A beta monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of A beta and antagonize A beta aggregation, or raise A beta clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of A beta which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against A beta oligomers have exhibited exciting findings. Nevertheless, A beta oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease A beta monomer or A beta plaques ought to have displayed valuable clinical benefits. In this article, A beta-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.