Title : A critical appraisal of strategies to afford protection against neurotoxic amyloid β peptides-induced brain degeneration
Abstract:
The 2022 world Alzheimer’s report pointed out the importance of early detection and diagnosis of Alzheimer’s disease (AD), as nearly 75% of individuals with dementia are not diagnosed globally. The histopathological hallmarks of AD are the extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles. The neurotoxic Aβ peptide Aβ(1-42), which is found in higher concentrations in the brain of AD patients and associated with Aβ plaques, is produced from the amyloid precursor protein (APP) by the called Amyloidogenic Pathway through the sequential activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase. An enhanced activity of BACE1 and shift towards the amyloidogenic pathway of APP processing has been reported to be linked to several factors known to foster the neurodegeneration in AD-affected brains, like iron dyshomeostasis, brain oxidative stress, hypercholesterolemia, and brain hypoxia. Nevertheless, nearly all BACE1 inhibitors used as candidate therapeutic agents in AD have failed in later phases of clinical trials, due to safety and/or efficacy issues, and others were discontinued early. Thus, exploration of alternate approaches to reduce Aβ toxicity seems a timely issue. Indeed, it has been noted recently that some phytochemicals that inhibit Aβ-induced neurotoxicity, Aβ self-aggregation, and acetylcholinesterase enzyme activity show anti-AD effects. Another novel potential therapeutic target for AD is the attenuation of signaling pathways leading to Aβ overproduction. The shortest Aβ(1-42)-derived peptide that retains the toxicity of the full-length peptide is Aβ(25-35), and this experimental observation is of particular relevance for the identification of peptides that can antagonize the actions of neurotoxic Aβ peptides. Cumulative experimental evidences show that intracellular Aβ oligomers are linked to AD pathogenesis and are the cause of neuronal damage, moreover, the metabolic and neurotoxic effects of Aβ(1-42) have been linked with neuronal uptake of Aβ oligomers and the subsequent rise of their intracellular concentration. As anti-Aβ antibodies are expected to trap only extracellular Aβ, this could, at least in part, account for the limited and partial protection reported for aducanumab treatment in AD. The studies performed in vitro, ex-vivo with cellular cultures and in vivo with animal models of AD open new perspectives for the clinical management of AD, and these are the main focus of this presentation. Also, the current limitations and need of further research studies for the translational application of these findings will be briefly discussed.
