Amyloid-beta aggregation implicates multiple pathways in Alzheimer’s disease: Understanding the mechanisms

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative condition characterized by tau pathology and accumulations of neurofibrillary tangles (NFTs) along with amyloid-beta (Aβ). It has been associated with neuronal damage, synaptic dysfunction, and cognitive deficits. The current review explained the molecular mechanisms behind the implications of Aβ aggregation in AD via multiple events. Beta (β) and gamma (γ) secretases hydrolyzed amyloid precursor protein (APP) to produce Aβ, which then clumps together to form Aβ fibrils. The fibrils increase oxidative stress, inflammatory cascade, and caspase activation to cause hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), which ultimately lead to neuronal damage. Acetylcholine (Ach) degradation is accelerated by upstream regulation of the acetylcholinesterase (AChE) enzyme, which leads to a deficiency in neurotransmitters and cognitive impairment. There are presently no efficient or disease-modifying medications for AD. It is necessary to advance AD research to suggest novel compounds for treatment and prevention. Prospectively, it might be reasonable to conduct clinical trials with unclean medicines that have a range of effects, including anti-amyloid and anti-tau, neurotransmitter modulation, anti-neuroinflammatory, neuroprotective, and cognitive enhancement.

A comprehensive bibliometric analysis of global research on the role of acrolein in Alzheimer’s disease pathogenesis: involvement of amyloid-beta

“…Amyloid-beta is a peptide that aggregates to form plaques in the brains of individuals with AD ( Chen et al, 2017 ). Aβ aggregation has been shown to implicate multiple pathways in AD, including oxidative stress, inflammatory cascade, and caspase activation, which ultimately lead to neuronal damage ( Sehar et al, 2022 ; Iliyasu et al, 2023 ). Mounting evidence indicates that the processing of APP is influenced by endocytosis and intracellular sorting ( Rajendran et al, 2006 ; Chaufty et al, 2012 ).…”

Alzheimer's Disease: Status of Low‐Dimensional Nanotherapeutic Materials

“…Subsequently, 𝛾-secretase performs another cleavage at the C-terminus, producing A𝛽1-40 and A𝛽1-42. [42][43][44][45][46] Such the intracellular cleavage of APP by the proteolytic enzymes 𝛽-secretase and 𝛾-secretase produces the short peptide known as A𝛽 with 40-42 amino acids, of which the A𝛽1-40 is the major species and the A𝛽1-42 is the most fibrillogenic and predominant component in AD plaques. [45] Besides, gene mutations also increase the production of A𝛽.…”

“…[39,[47][48][49][50][51][52] The differential lipidation status exhibited by apolipoprotein E (ApoE) isoforms such as ApoE4 (E4), ApoE3 (E3), and ApoE2 regulates A𝛽's accumulation and lessens its clearance by stimulating cellular uptake and degradation of ApoE-A𝛽 complexes from the brain (E4 > E3 and E2). [46] The accumulation of toxic A𝛽 induced by the imbalance of production and elimination can damage neurons and synapses in the brain through various mechanisms. They include the upregulation of the receptor for advanced glycation end products (RAGE) leading to neurotoxicity.…”

“…[93][94] Other mentals like Fe 3+ , Mn 2+ , Pb 2+ , Cd 2+ , Hg 2+ , and Al 3+ also stimulate amyloidogenic pathways and A𝛽 aggregation. [46] Excessive levels of transition-metal ions reacting with oxygen such as Cu 2+ can catalyze the generation of cytotoxic ROS and thereafter induce neuronal cell apoptosis. [75,95] Nevertheless, due to the limited understanding of the precise involvement of metal dyshomeostasis and its interaction with other pathological factors, it is crucial to propose effective metal chelation therapy as a mean to restore homeostasis in Alzheimer's disease (AD).…”

Fluorimetric Detection of Insulin Misfolding by Probes Derived from Functionalized Fluorene Frameworks

“…These toxic residues are associated with different pathologies in which an abnormal protein is the main trigger of diseases such as diabetes and cancer [ 2 , 3 , 4 ]. Aberrant conformations of the proteins β-amyloid [ 5 ], tau [ 6 ], α-synuclein [ 7 ], huntingtin [ 8 ], fused in sarcoma (FUS) [ 9 ], and TDP-43 [ 10 ] proteins are responsible for the symptomatology of the most prominent neurodegenerative disorders [ 11 ], such as Alzheimer’s, Parkinson’s, and Huntington’s diseases and amyotrophic lateral sclerosis, while infective prion proteins [ 12 ] cause irreversible spongiform encephalopathy [ 13 , 14 ].…”