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  • Perforation of the surface membrane however is not the only

    2022-11-18

    Perforation of the surface membrane, however, is not the only mechanism of calcium dysregulation by Aβ at the presynaptic terminals. When in excess, both monomers and oligomers modulate biophysical properties of voltage-activated calcium L-Stepholidine australia as well as calcium release from the endoplasmic reticulum, with knock-on effects on transmitter release and synaptic plasticity [125,128]. Rapid and localized calcium influx mediated via voltage-gated N- or P/Q-type calcium channels at presynaptic terminals are the principal regulators of transmitter release, coupled also to postfusion membrane recovery. In all neuron types tested, Aβ modulates voltage-gated calcium currents [83]. In cortical synapses, for instance, low concentrations (10 nM) of Aβ42 oligomers enhance spontaneous release of glutamate and noradrenaline, which can be reversed by an N-type channel blocker ω-conotoxin GVIA but not by ω-agatoxin or diltiazem, inhibitors of P/Q- and L-type calcium channels [15]. Under prolonged Aβ42 treatment, however, significant inhibition of N-type calcium was also observed [55]. In cerebellar granule cells, at potentials positive to 0 mV, calcium currents are significantly enhanced by prolonged exposure to 1-μΜ Aβ [102]. The increase in calcium currents was accompanied by a 5-mV shift in channel activation in the positive direction and increased deactivation. Similarly, in cortical neurons, inhibition of L-type channels with nifedipine (2 μM) did not prevent the rise in calcium channel currents or affect current activation and deactivation. N-type calcium channel antagonist ω-conotoxin GVIA (1 μM), on the other hand, abolished the augmentation of Ca2+ current and deactivation rate changes but failed to encounter the shift in the current activation curve. These data suggest that Aβ could exert presynaptic effects via disruption of calcium influx through N-type calcium channels. Subsequent reports showed that in cortical neurons, both monomeric and oligomeric Aβ40 facilitate P-type calcium currents [73], while their effects on N-type channels depend on the Aβ aggregation state, causing bilateral changes [107]. Interestingly, a more recent study in cultured hippocampal neurons demonstrated that at micromolar dose, Aβ42 oligomers inhibit P/Q-type calcium currents [84], while the same preparation of Aβ increased P/Q-type calcium channel currents expressed in Xenopus laevis[78]. This discrepancy could be due to the fact that in an expression system, enhanced effects of Aβ40 oligomers are due to direct interaction of Aβ with the Cav2.1 α-subunit of the P/Q-type channel, in the absence of axillary subunits [83]. Functional measurements of the effects of Aβ42 oligomers via Ca2+ channels showed inhibition of spontaneous postsynaptic currents, an outcome that could be partly attributed to the reduction of calcium-dependent transmitter release at presynaptic terminals [84]. In light of the key regulatory functions of N- and P/Q-type calcium currents in transmitter release, changes in presynaptic Ca2+ currents induced by Aβ are expected to have a major impact on synaptic transmission and plasticity mechanisms, with knock-on effects on neural circuit dynamics and information processing.
    Concluding remark The SVC plays a twofold role in the pathobiology of AD. On one side, it facilitates the amyloidogenic processing of APP by β-secretase BACE1 and γ-secretase complex, leading to Aβ production and release. On the other hand, it presents the prime target for Aβ toxicity, resulting in failure of synaptic function and leading to degeneration of synaptic connections. Throughout this review, we considered and discussed emerging data illustrating the effects of Aβ on major steps in the SVC, from postfusion membrane recovery to vesicle trafficking, docking, and fusion as well as on presynaptic voltage-gated calcium currents. Conceivably, the most important notion that threads across most studies reviewed here is that SVC (and neurotransmitter release) is subject to regulation by both, extracellular and intracellular Aβ. In fact, the early onset of functional changes associated with the rise in intracellular Aβ, in the absence of extracellular amyloid deposits, emerges to be of major relevance to cognitive impairments and changes in neural network dynamics in preclinical AD. At more advanced stages, these alterations become aggravated by the added effects of extracellular Aβ, disturbing all major synaptic functions and plasticity mechanisms, leading to the collapse of dendritic spines and loss of synaptic connections. From the above discussion, it follows that in addition to the most widely used therapeutic approaches targeting Aβ production and clearance mechanisms by developing specific APP protease inhibitors and anti-Aβ immunotherapies, modulators of Aβ uptake mechanisms and presynaptic Ca2+ channel functions as well as inhibitors of the translocation of Aβ into the neuronal cytosol could hold major therapeutic potential. Dampening the hyperactivity of cortical circuits and acceleration of the extracellular glutamate clearance are other areas of potential interest, given the tight coupling between the synaptic activity with Aβ release and plaque formation [91,95,142]. While still at the premature stage, research into this “Frankensteinian” drama unfolding at axon terminals, where the product of synaptic activity Aβ relentlessly degrades all core synaptic functions and mechanisms has already shown great promise for clarifying major facets of the pathobiology of AD, for better understanding and possibly management of this highly complex brain disorder.