Alzheimer’s Disease: A Molecular View of β-Amyloid Induced Morbific Events

Abstract

Amyloid-β (Aβ) is a dynamic peptide of Alzheimer’s disease (AD) which accelerates the disease progression. At the cell membrane and cell compartments, the amyloid precursor protein (APP) undergoes amyloidogenic cleavage by β- and γ-secretases and engenders the Aβ. In addition, externally produced Aβ gets inside the cells by receptors mediated internalization. An elevated amount of Aβ yields spontaneous aggregation which causes organelles impairment. Aβ stimulates the hyperphosphorylation of tau protein via acceleration by several kinases. Aβ travels to the mitochondria and interacts with its functional complexes, which impairs the mitochondrial function leading to the activation of apoptotic signaling cascade. Aβ disrupts the Ca2+ and protein homeostasis of the endoplasmic reticulum (ER) and Golgi complex (GC) that promotes the organelle stress and inhibits its stress recovery machinery such as unfolded protein response (UPR) and ER-associated degradation (ERAD). At lysosome, Aβ precedes autophagy dysfunction upon interacting with autophagy molecules. Interestingly, Aβ act as a transcription regulator as well as inhibits telomerase activity. Both Aβ and p-tau interaction with neuronal and glial receptors elevate the inflammatory molecules and persuade inflammation. Here, we have expounded the Aβ mediated events in the cells and its cosmopolitan role on neurodegeneration, and the current clinical status of anti-amyloid therapy.

Inflammatory Processes in Alzheimer’s Disease—Pathomechanism, Diagnosis and Treatment: A Review

“…It can therefore stimulate native CNS immune cells to induce an inflammatory reaction against the accumulating β-amyloid that forms the deposits surrounding these cells. In order for the complement system to be activated, β-amyloid must be properly fibrillated [ 72 ].…”

New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

“…Aβ can be produced intracellularly by APP cleavage. External Aβ can enter the cells by receptor-mediated internalization [ 40 ]. Aβ monomers start to aggregate into different Aβ oligomers over a critical concentration [ 41 ].…”

“…The most important pathogenic events induced by toxic oAβ are (1) stimulation of tau-hyperphosphorylation, (2) impairment of mitochondrial function, (3) disruption of Ca 2+ and protein homeostasis, and (4) induction of autophagy dysfunction. [ 40 ].…”

Recent Advances in Our Molecular and Mechanistic Understanding of Misfolded Cellular Proteins in Alzheimer’s Disease (AD) and Prion Disease (PrD)

“…The 695–751 amino acid beta-amyloid precursor protein (βAPP; encoded at human chromosome 21q21.3; ; last accessed 18 January 2022), a Type 1 integral trans-membrane protein, is endoproteolytically processed to generate either the neurotrophic secreted ectodomain constituting APP alpha (sAPPα) or a series of ragged, neurotoxic, amyoidogenic amyloid beta (Aβ) peptides [ 18 , 19 ]. The 40–42 amino acid amyloid-beta (Aβ40, Aβ42) peptides and other oligomeric Aβ species are derived from the sequential tandem endoproteolytic cleavage of βAPP by the amyloidogenic beta- and gamma-secretases [ 18 , 19 , 20 , 21 ]. While the neurobiology and neurophysiology of βAPP holoprotein is incompletely understood, βAPP’s most recent functional assignments include essential roles in cellular adhesion, neural growth and repair, neurogenesis, synaptic plasticity, neurite outgrowth and/or neuroprotection, and many of these neurotrophic functions are moderated by the α-secretase-mediated βAPP ectodomain cleavage into sAPPα [ 17 , 18 , 20 , 21 ].…”

“…The 40–42 amino acid amyloid-beta (Aβ40, Aβ42) peptides and other oligomeric Aβ species are derived from the sequential tandem endoproteolytic cleavage of βAPP by the amyloidogenic beta- and gamma-secretases [ 18 , 19 , 20 , 21 ]. While the neurobiology and neurophysiology of βAPP holoprotein is incompletely understood, βAPP’s most recent functional assignments include essential roles in cellular adhesion, neural growth and repair, neurogenesis, synaptic plasticity, neurite outgrowth and/or neuroprotection, and many of these neurotrophic functions are moderated by the α-secretase-mediated βAPP ectodomain cleavage into sAPPα [ 17 , 18 , 20 , 21 ].…”