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    • br Obstructing SNARE zippering Sharma

    2024-02-20


    Obstructing SNARE “zippering” Sharma et al. demonstrated for the first time that in the postmortem AD brains, the level of SNARE complex formation, which is necessary for driving synaptic vesicle fusion at the presynaptic active zone, is significantly reduced [123]. In the absence of changes in expression of individual SNARE proteins in their study, this finding has been interpreted as evidence that Aβ hinders the “zippering” of vesicle SNARE (v-SNARE) VAMP-2 with target SNAREs (t-SNARE) syntaxin-1 and soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)-25 into a four-helical SNARE complex (Fig. 2A). Such effects of Aβ could contribute toward a wide range of synaptic impairments and network dysfunctions found in AD [5,97]. In the search for molecular correlates of this effect, Yang et al. recently analyzed the impact of Aβ42 monomers and oligomers on SNARE complex formation in APP-PS1 mice, using biochemical assays in vitro and a transgenic approach in vivo [144] (Fig. 2B and C). As APP-PS1 mice are engineered to overexpress Aβ but no other AD-related proteins (e.g., tau, presenilin) [48], they are very suitable as a model for exploring specific effects of pathologically enhanced levels of Aβ on SNARE interactions. In APP-PS1 mice, like in humans, the Western blot bands corresponding to the super-stable SNARE complex are significantly reduced, without a change in the expression of SNARE proteins. The outcome of these biochemical experiments is in agreement with functional data, which demonstrate inhibition of Bazedoxifene HCl by intracellular Aβ42 oligomers [79]. Detailed analysis of Aβ interactions with v-SNAREs and t-SNAREs showed that the hampering effects of Aβ42 oligomers on SNARE complex formation were due to its high-affinity interactions with t-SNARE syntaxin 1a, and specifically with the SynH3 motif, known to play a critical role in the formation of four-helical SNARE bundles [100,129] (Fig. 2D and E). Indeed, it is the disruption of the association of syntaxin-1 with VAMP-2 and SNAP-25 that limits the formation of the trans-SNARE complex, essential for setting vesicle fusion into motion. In similar experiments with Aβ42 monomers, while Aβ42 displayed the ability to interact with syntaxin-1, it failed to prevent the formation of the sodium dodecyl sulfate–resistant SNARE complex or membrane fusion reaction, implying the unique capability of Aβ42 oligomers to interfere with the assembly of SNAREs and exocytosis [144]. Intriguingly, no evidence was found for impairments of synaptic vesicle docking by either Aβ monomers or oligomers, an observation that suggests the differential sensitivity of synaptic vesicle docking and fusion to Aβ [144]. Given the pivotal role of t-SNARE syntaxin-1 in synaptic vesicle docking, the differential effects of Aβ on docking versus fusion have been interpreted as a result of steric hindrance of Aβ oligomers (but not monomers) to “zippering” of SNAREs into a four-helix complex (cis-SNARE), while sparing their partial assembly required for docking (trans-SNARE) (Fig. 3D and E). In this context, it is worth stressing that presynaptic terminals represent the principal site of Aβ reuptake, which may subsequently leak from early and recycling endosomes into the cytoplasm [66,112]. As mentioned above, in hippocampal neurons, internalized Aβ42 interferes with specific interactions between synaptophysin and VAMP-2, which is essential in priming synaptic vesicles for regulated exocytosis, another major step in SVC [112]. These findings agree with functional measurements detailed in the following sections, consolidating the disruptive effects of Aβ on synaptic vesicles trafficking and recovery after fusion.
    Synaptic vesicle recovery and trafficking Endocytosis is a critical step in the SVC, which affords recovery of the synaptic membrane after exocytosis. Four main types of endocytosis have been defined, with clathrin-dependent endocytosis enabling the retrieval of synaptic vesicles. In neurons, this process is controlled by a set of regulatory and adaptor proteins (AP-2, AP-180, dynamin, epsin, and others), which promotes the fission, pinching off, and uncoating of the surface membrane followed by formation of synaptic vesicles [113,143]. Considerable evidence suggests that in AD, clathrin-dependent recovery of synaptic vesicles may be severely compromised [141,145], with both genomic and proteomic studies showing also reduced expression of regulator proteins in AD autopsies [145–147]. Indeed, analysis of the expression of dynamin 1, AP180, and synaptophysin across various brain regions showed a notable decrease in their levels in the hippocampal CA1 region and the entorhinal cortex. The expression of AP180 and synaptophysin was also lower in the hippocampal dentate gyrus and CA4 region, as well as in the wider temporal cortex.