Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

Abstract

Amyloidogenesis has been implicated in a broad spectrum of diseases in which amyloid protein is invariably misfolded and deposited in cells and organs. Alzheimer's disease is one of the most devastating ailments among amyloidogenesis induced dementia. The amyloid beta (Aβ) peptide derived from amyloid precursor protein (APP) is misfolded and deposited as plaques in the brain, which are said to be the hallmark of Alzheimer's disease. In normal brains physiological concentration of the Aβ peptide has been indicated to be involved in modulating neurogenesis and synaptic plasticity. However, excess Aβ production, its aggregation and deposition deleteriously affect a large number of biologically important pathways leading to neuronal cell death. Targeting Aβ production, Aβ aggregation or its clearance from the brain has been an active area of research for preventing or curing AD. Our Feature Article intends to detail the aggregation mechanism, the physiological role of the Aβ peptide, elaborate its toxic effects, and outline the different classes of molecules designed in the last two years to inhibit amyloidogenic APP processing, Aβ oligomerization or fibrillogenesis and to modulate different pathways for active clearance of Aβ from the brain.

Transthyretin Mimetics as Anti‐β‐Amyloid Agents: A Comparison of Peptide and Protein Approaches

“…[3] However, most of these Aβ aggregation inhibitors have modest affinity and require stoichiometric or greater quantities; furthermore, selectivity and specificity are often unreported, and none have proved to be clinically effective. [3, 4] …”

“…[6] Monoclonal antibodies offer higher affinity and excellent specificity ; several anti-Aβ antibodies (such as bapineuzumab and solanezumab) have been developed that showed promise in animal studies but have been largely unsuccessful in clinical trials. [3e, 7] Antibodies that specifically target Aβ oligomers and aggregates, rather than monomers, may be an essential feature for clinical success. [7d] Drawbacks of monoclonal (or other protein therapeutics) include poor oral bioavailability, high cost, and susceptibility to proteolysis.…”

“…[3a,d,f–h, 5, 8] Alternatively, Aβ-binding peptides have been identified by screening phage-display libraries. [3f, 9] Our strategy for designing anti-Aβ agents is distinct from these other approaches (Figure 1). We start with evidence, from animal studies, that transthyretin (TTR) overexpression protects against Aβ deposition and toxicity.…”

Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing α/β and α/γ Hybrid Peptidomimetics

“…The non-toxic native monomer of hIAPP misfold to β-sheet rich oligomer which perform membrane fragmentation and destroy the pancreatic β-cells by pore formation910. Therefore, blocking the ability of the amyloidogenic peptide to adopt a β-sheet rich conformation and impairment of the toxic oligomers would be an important strategy to inhibit the amyloid formation and drug development against T2DM and other amyloid related diseases11121314.…”

Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity

“…Poor understanding of the molecular mechanisms involved in disease pathogenesis and absence of early diagnosis delayed the development of effective therapeutics to cure or prevent the progression of AD. [3][4][5] Currently, approved drugs for AD provide only symptomatic and temporary relief without affecting the core pathogenesis. 6 Therefore, developing therapeutic agents that preferentially act on the disease-causing pathways are the need of the moment.…”