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.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease, and globally, over 46 million people are affected by this devastating disease [1,2]
Mutations in PSEN seem to be the major cause of familial AD (FAD) with over 150 causative mutations that have been mapped to the genes (PSEN1 and PSEN2) encoding the PSEN proteins [62,63]
In clinical trials, when gantenerumab was administered to moderate AD individuals, it decreased the load of brain amyloid by up to 30% as estimated via a positron emission tomography scan, but 2 individuals experienced vasogenic cerebral edema in the high dose group [248]
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease, and globally, over 46 million people are affected by this devastating disease [1,2]. To decrease the social and economic costs and the burden of the disease on patients and their families, recently, several attempts have been made to identify disease diagnostic markers [8] Neuroimaging methods, such as magnetic resonance imaging and positron emission tomography, have been developed enabling researchers to diagnose AD at the early stages of the disease. The advancement of AD is associated with three cardinal neuropathological features such as extracellular deposition of amyloid-β (Aβ) to produce neuritic plaques, intracellular neurofibrillary tangles (NFTs) and synaptic degeneration [11,12,13] These pathological alterations arise in the neocortex, hippocampus, and other subcortical regions that are crucial for cognitive functions [14]. We have critically reviewed the recent studies targeting Aβ in Alzheimer’s pathogenesis
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