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

Abstract

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-β (Aβ), a peptide of 40-42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ 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 Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ 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 Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

Keywords: Alzheimer’s disease; Aβ; BAN2401; aducanumab; amyloid precursor protein; tau.

Figure 1

Processing of APP by secretases that leads to the formation of Alzheimer’s-associated Aβ peptides. In the amyloidogenic pathway, APP is cleaved by β- and γ-secretases leading to the formation of Aβ peptides and AICD. Formation of the neurotoxic Aβ is the major cause of AD. In the non-amyloidogenic pathway, APP is cleaved by α- and γ-secretases leading to the genesis of p3 and AICD. APP, Amyloid precursor protein; sAPPα, Soluble APP alpha; sAPPβ, Soluble APP beta; αCTF 83, Alpha C-terminal fragment 83; βCTF 99, Beta C-terminal fragment 99; AICD, APP intracellular domain.