Exploring the Potential of Therapeutic Agents Targeted towards Mitigating the Events Associated with Amyloid-β Cascade in Alzheimer’s Disease

Abstract

One of the most commonly occurring neurodegenerative disorders, Alzheimer’s disease (AD), encompasses the loss of cognitive and memory potential, impaired learning, dementia and behavioral defects, and has been prevalent since the 1900s. The accelerating occurrence of AD is expected to reach 65.7 million by 2030. The disease results in neural atrophy and disrupted inter-neuronal connections. Amongst multiple AD pathogenesis hypotheses, the amyloid beta (Aβ) cascade is the most relevant and accepted form of the hypothesis, which suggests that Aβ monomers are formed as a result of the cleavage of amyloid precursor protein (APP), followed by the conversion of these monomers to toxic oligomers, which in turn develop β-sheets, fibrils and plaques. The review targets the events in the amyloid hypothesis and elaborates suitable therapeutic agents that function by hindering the steps of plaque formation and lowering Aβ levels in the brain. The authors discuss treatment possibilities, including the inhibition of β- and γ-secretase-mediated enzymatic cleavage of APP, the immune response generating active immunotherapy and passive immunotherapeutic approaches targeting monoclonal antibodies towards Aβ aggregates, the removal of amyloid aggregates by the activation of enzymatic pathways or the regulation of Aβ circulation, glucagon-like peptide-1 (GLP-1)-mediated curbed accumulation and the neurotoxic potential of Aβ aggregates, bapineuzumab-mediated vascular permeability alterations, statin-mediated Aβ peptide degradation, the potential role of ibuprofen and the significance of natural drugs and dyes in hindering the amyloid cascade events. Thus, the authors aim to highlight the treatment perspective, targeting the amyloid hypothesis, while simultaneously emphasizing the need to conduct further investigations, in order to provide an opportunity to neurologists to develop novel and reliable treatment therapies for the retardation of AD progression.

Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

“…Keywords TDP-43 • Tau • Amyloid-β (Aβ) • Alzheimer's disease • Limbic-predominant age-related TDP-43 encephalopathy (LATE) • Frontotemporal lobar degeneration (FTLD) Perspectives Pathophysiological spectrum in Alzheimer's disease Alzheimer's disease (AD), a devastating, fatal neurodegenerative disease of aging, features the presence of extracellular amyloid-β (Aβ) plaques and intracellular tangles of hyperphosphorylated tau in the brain [1].For decades, prevention or clearance of Aβ plaques have been the major therapeutic goals in the pursuit of a treatment for AD. This was a rational approach given that mutations in genes involved in amyloid processes cause some inherited (familial) cases of AD [2]. Unfortunately, most clinical trials have failed thus far to demonstrate a significant benefit to patients, raising the need to pursue additional strategies [3].…”

Administering crocin ameliorates anxiety‐like behaviours and reduces the inflammatory response in amyloid‐beta induced neurotoxicity in rat

“…van der Stelt et al 37 has shown that twelve days after the injection of β‐amyloid into the frontal cortex result in neuronal impairment in the hippocampus (CA1, CA2 and CA3 areas). Moreover, the Aβ cascade hypothesis is the most relevant and accepted theory related to AD pathophysiology, which are formed by the misfolding of Aβ monomers 39 . Therefore, on the basis of these studies, a rat model of the AD was used by bilateral injection of β‐amyloid into the frontal cortex and effects of crocin were investigated in the CA1 region.…”

“…Moreover, the Aβ cascade hypothesis is the most relevant and accepted theory related to AD pathophysiology, which are formed by the misfolding of Aβ monomers. 39 Therefore, on the basis of these…”

Elucidating the Multi-Targeted Role of Nutraceuticals: A Complementary Therapy to Starve Neurodegenerative Diseases

“…Thought to start 20 years or more before, the symptoms arise with brain alterations that remain unnoticeable to the affected person. Individuals after years of brain alterations experience noticeable symptoms (i.e., language problems and memory loss) [ 26 , 27 , 28 , 29 ]. The occurrence of symptoms is due to damage or destruction of nerve cells (neurons) in brain regions involved in learning, thinking, and memory [ 26 , 30 , 31 ].…”