Soluble Aβ Oligomers Formed Channels Leading to Calcium Dysregulation

essi v el y impairs cogniti v e function,

ous forms of A β oligomers is considered a significant factor in AD pr ogr ession. Recent FDA-appr ov ed anti-amyloid drugs (Aducan uma b and Lecanemab) selectively target amyloid aggregates. The calcium dysregulation hypothesis suggests that abnormal handling of Ca 2 + in neurons contributes to AD's development. 1 , 2 Disruptions in calcium homeostasis lead to neuronal dysfunction, synaptic damage, and death. Evidence points to the inv olv ement of calcium-r elated r ece ptors in AD. These r ece ptors include N-Methyl-D-Aspartate (NMDA) r ece ptors, v olta ge-gated calcium channels (VGCCs), and the upregulation of ryanodine r ece ptors and inositol triphosphate r ece ptors.
In this journal, Li et al. (2023) 3 r ev ealed that endogenous A β can form Ca 2 + -permea b le channels in aged 3xTg AD mice. By employing patc h-clamp tec hniques, the authors observed spontaneous Ca 2 + oscillations in pancreatic acinar cells of aged 3xTg AD mice, where VGCCs are not typically present, while no such oscillations were seen in age-matched wild-type mice. Through the utilization of perforated patch recording, it was demonstrated that the application of A β in the r ecording electr ode can effecti v el y permeate the cellular membrane and create a pore on dissociated adult acinar cells. Inter estingl y, they discov er ed that the Ca 2 + oscillations can be eliminated by removing extracellular Ca 2 + , adding ZnCl 2 , or using the A β channel blocker Anle138b. Their subsequent investigation revealed that these spontaneous Ca 2 + oscillations were mediated through Ca 2 +induced Ca 2 + release (CICR) rather than InsP3-induced Ca 2 + r elease. Nota b l y, these oscillations differ ed fr om acetylcholine (ACh)-induced spontaneous Ca 2 + oscillations. In contrast to previous r e ports wher e high concentrations of e xo genous A β were used to form A β channels or pores in vitro, this study suggests the presence of endogenously mediated A β channels.
To investigate the formation of Ca 2 + -permea b le channels by A β, the authors made a prudent decision by selecting pancreatic acinar cells, which typically lack VGCCs but accumulate A β deposition, similar to the hippocampus. However, it is worth noting that hippocampal neur ons hav e n umer ous VGCCs. To eliminate the possibility of intracellular Ca 2 + elevation due to digesti v e enzyme acti vity in pancr eatic acinar cells, the authors conducted additional experiments on ACh, a common r ece ptor for secretion in these cells. Interestingly, they observed that the specific Ca 2 + oscillations mentioned earlier were not affected by atropine, an ACh r ece ptor anta gonist. The Ca 2 + oscillations induced by ACh were completely blocked by the same concentration of atropine. Of great significance, the Ca 2 + oscillations induced by A β (both endogenous and e xo genous) ar e markedl y distinct from ACh-induced oscillations. The A β-induced oscillations necessitate extracellular Ca 2 + influx and elicit CICR. Conv ersel y, the ACh-induced oscillations are unaffected by extracellular Ca 2 + influx and Anle138b. Thus, the initiation and pharmacological response of A β-induced Ca 2 + oscillations differ from those of ACh-induced Ca 2 + oscillations.
It is widely accepted that the primary toxic species affecting brain cells are the soluble A β oligomers, instead of the monomers or plaques. These A β oligomers exert their influence by interacting with their partners on cell membranes, leading to dysfunction in various membrane proteins (such as cellular prion protein, NMDAR, AMPAR, mGluRs, α7nAChR, the receptor for advanced glycation endproducts and insulin receptor). 4 , 5 Several studies have also revealed that the A β oligomers possess the ability to create ion channel pores known as A β ion channels. 6 Previous studies on A β ion channels hav e primaril y 1 Figure 1. Schematic of the principal pathways identified for endogenous A β-formed Ca 2 + -permea b le channels. A β oligomers engage with the cell membrane and create "ion pores," facilitating the entry of extracellular Ca 2 + into the cell. These Ca 2 + ions, in turn, trigger additional Ca 2 + release from the endoplasmic reticulum, leading to an increase in intracellular Ca 2 + levels. This rise in Ca 2 + levels results in an observable oscillation wave that can be recorded using patch clamp techniques.
focused on in vitro experiments involving both artificial and natur al membr anes, wherein high concentr ations (r anging from 2 to 15 μm ) of soluble A βw ere employ ed. A recent re vie w has compr ehensi v el y outlined the process of A β ion channel pore formation based on cutting-edge techniques such as cr yo-electr on tomography imaging, transmission electron microscopy, and atomic force microscopy. 7 According to the findings, two distinct types of pores are formed by A β oligomers. Firstly, A β annular oligomers are seen to insert into the membr ane , consequently forming ion channel por es. Secondl y, ther e ar e A β curvilinear protofibrils and oligomers that spread out and embed themselves within the bilayer, leading to membrane permeability and lipid extraction akin to a detergent-like effect. The formation of A β ion channels facilitates the influx of Ca 2 + ions, which in turn triggers the release of intracellularly stored Ca 2 + . Consequently, this disturbance in Ca 2 + homeostasis leads to imbalances and a berrant acti vity within the signaling pathw ays, leading to perturbations in cellular function ( Figure 1 ). It is important to note that in the current study, Anle138b was used as a blocker for A β ion channels, 8 whereas earlier studies utilized tromethamine and aluminum to block A β-induced Ca 2 + channels. 9 As of now, there are no approved drugs or compounds specifically designed as A β c hannel bloc kers for clinical use . How ever, Anle138b, a small organic molecule, has exhibited pr omising r esults in pr eclinical studies inv olving animal models of neurode gener ative diseases, including AD. It has been investigated for its potential to inhibit the a ggr egation and spr ead of misfolded proteins, such as α-synuclein in Parkinson's disease and prions in prion diseases. Although Anle138b primarily targets protein aggregation and propagation, it does not selectively bloc k A β c hannels. Its mec hanism of action inv olv es sta bilizing the structure of misfolded proteins and preventing their harmful effects. By combining v olta ge or curr ent pr otocols with wellknown ion channel blockers and applying them to the membr ane patc h, different types of ion c hannels can be selecti v el y acti v ated. This allows for the specific measurement of their activity, facilitating the detection of A β-induced Ca 2 + channels.
In the present study, Li et al. 3

discov er ed that endogenous
A β oligomers possess the capability to create a Ca 2 + channel, thereby disrupting the delicate balance of Ca 2 + levels within cells. This finding contributes to our comprehension of the existing literature on the hypothesis of calcium dysregulation 1 , 2 and the role of A β-interact with membrane proteins 4 , 5 in the etiology of AD. Further examination of the c har acteristics and mechanisms of A β-generated Ca 2 + channels in neurons could yield significant insights into the molecular mechanisms underlying AD and its associated pathophysiological features. Consequentl y, this inv estigation esta b lishes a foundation for futur e resear c h investigating the impact of A β on Ca 2 + functionality in animal models of AD, with the expectation that such studies will illuminate potential therapeutic targets for the effecti v e treatment of AD.