Beta‐amyloid pore linked to controlled calcium influx into the cell: A new paradigm for Alzheimer's Disease

Abstract

Despite tremendous worldwide efforts, clinical trials assessing Alzheimer's disease (AD)‐related therapeutics have been relentlessly unsuccessful. Hence, there is an urgent need to challenge old hypotheses with novel paradigms. An emerging concept is that the amyloid‐beta (Aβ) peptide, which was until recently deemed a major player in the cause of AD, may instead modulate synaptic plasticity and protect against excitotoxicity. The link between Aβ‐mediated synaptic plasticity and Aβ trafficking is central for understanding AD pathogenesis and remains a perplexing relationship. The crossover between Aβ pathological and physiological roles is subtle and remains controversial. Based on existing literature, as a signaling molecule, Aβ is proposed to modulate its own turnover and synaptic plasticity through what is currently believed to be the cause of AD: the transient formation of pore‐like oligomers. A change of perspective regarding how Aβ pores exert a protective function will unavoidably revolutionize the entire field of anti‐amyloid drug development.

Molecular insights into the oligomerization dynamics and conformations of amyloidogenic and non-amyloidogenic amylin from discrete molecular dynamics simulations

“…The β-barrel aggregates first observed in an 11-residue peptide derived from the slow-aggregating αB crystalline form have been proposed as toxic oligomers of amyloid aggregation 55 due to their well-defined structures and compatibility to the “amyloid-pore” 56 hypothesis of amyloid toxicity. 44,50 The formation of β-barrel oligomers by full-length Aβ peptides was supported by hydrogen exchange mass spectrometry, NMR measurement, cryo-EM essays, and computational simulations.…”

“…Interestingly, hIAPP and hIAPP(S20G) could form β-barrel formations, which were proposed as toxic oligomers of amyloid aggregation. 6,49–52,55,56 The β-barrel propensity of hIAPP(S20G) was three times larger than that of hIAPP. Another recent experimental study using transmission electron microscopy (TEM) imaging also demonstrated that the barrel-like oligomers of hIAPP(S20G) were more abundant than hIAPP wild-type.…”

Identification of hub genes associated with cognition in the hippocampus of Alzheimer’s Disease

“…Numerous basic and clinical studies have demonstrated the direct role of synapse in cognitive impairment. At the biological level, the synaptic function is distorted in the settings of neurogenerative diseases, especially the ‘synaptic plasticity’ in AD [ 25 ]. Synaptic plasticity is closely associated with the formation of learning and memory [ 26 ].…”

Human stefin B: from its structure, folding, and aggregation to its function in health and disease

“…aggregation, and pore formation (see Table 1). Together, these would trigger initial events [e.g., mitochondrial dysfunction with calcium influx (Pannuzzo, 2022), oxidative stress] followed by somewhat downstream endosomal/lysosomal dysfunction (Lee et al, 2022) again to more mitochondrial ROS and systemic inflammation). However, a counter-argument to such a hypothesis is that no protein aggregates, or amyloid fibrils, have been detected in EPM1 patient cells, whether from neurons or glia, or animal models.…”