Similar studies in Swedish Mutation of APP

Similar studies in Swedish Mutation of APP AD transgenic mice revealed reduced dynamin 1, AP180, and synaptophysin expression in the hippocampus, particularly prominent in the CA1 and CA4 subfields [19]. These findings imply that Aβ can act not only as a modulator of exocytosis but is a potent regulator of synaptic vesicle recovery after fusion. It is interesting to note that reduction of dynamin 1 and synaptophysin was also observed in rats injected with Aβ42 into the hippocampus, with RNA and protein levels of AP180, however, unchanged or even elevated. Also, changes in dynamin-1 and AP180 expression under chronic elevation of the Aβ levels were far more pronounced than those of synaptophysin, implying that these effects result from downregulation of AP180 and dynamin 1 by Aβ42 and are not a by-product of synaptic degeneration [59]. Assessment of the functional effects of Aβ42 on stimulation-induced lasofoxifene synthesis and recovery of the synaptic membrane in neuronal cultures with FM1-43 fluorescence dye showed that in the presence of Aβ42, the dye uptake coupled with synaptic activity is markedly reduced [19]. This effect was attributed to the inhibition of dynamin 1 activity, as in similar experiments in control neurons (i.e., in the absence of Aβ42) postexocytosis membrane recovery was not altered. Reduced dynamin 1 and AP180 activity are likely to contribute toward the altered size of synaptic vesicle pools in AD mouse models and AD autopsies [19,99]. At a typical presynaptic terminal, three discrete but interconnected pools of synaptic vesicles can be distinguished: (1) releasable, (2) recycling, and (3) reserve, with all three of major relevance to synaptic physiology and plasticity [110]. Using vGlut-pHluorin fluorescence protein expression in cultured neurons, Park et al. observed a reduction of recycling and increase of the synaptic vesicle reserve pool by Aβ42 oligomers [98]. These effects occur without alterations in the total synaptic vesicle content of axon terminals. In a separate experiment, the effects of Aβ42 oligomers on the rate of endocytosis in individual synaptic boutons were analyzed, with endocytosis and reformation of synaptic vesicles found to be slowed down, leaving only 50% of released vesicles recycled back to the releasable pool [98]. Although the molecular mechanisms of delayed recovery of synaptic vesicles remain unclear, CDK5, known to regulate synaptic vesicle pool size [63], has been suggested to play a major role [98,132] (Fig. 3A–C). Aβ oligomers are shown to activate CDK5 via calpain, with levels of CDK5 in AD brain autopsies reported being significantly enhanced [70,105]. Failure of Aβ42 oligomers to inhibit endocytosis and alter the size of recycling and resting vesicle pools in the presence of CDK5 inhibitors is consistent with this mechanism [98]. Other factors such as depletion of dynamin 1 by Aβ oligomers [58] with knock-on effects on synaptic vesicle recovery and trafficking as well as vesicle exchange between different pools could also potentially contribute.
Voltage-gated calcium influx and Aβ Calcium is a ubiquitous regulator of neuronal functions, with intracellular Ca2+ dynamics tightly regulated by multiple presynaptic and postsynaptic mechanisms. The causative link between dysregulation of calcium homeostasis, brain aging, and AD was first proposed by Z. Khachaturian [60–62] in the calcium hypothesis of AD and brain aging [4,60]. According to this hypothesis, sustained disruptions of intracellular Ca2+ signaling are not only the key for triggering aging-related adverse changes in the functioning of neurons but are also crucial for the initiation of pathological processes underlying synaptic deficit and neurodegeneration of AD (Box 2). In turn, both Aβ monomers and oligomers have been shown to disrupt Ca2+ homeostasis, with oligomers capable of forming calcium-permeable pores, causing a pathological increase in the level of intracellular calcium, with cytotoxicity [6,7,65]. These reports received backing from biophysical studies, which demonstrated activation of transmembrane cation currents in cells exposed to Aβ oligomers [33,72], capable of disrupting the fine ionic balance and causing oxidative stress, which can lead to cell death. Increase in presynaptic Ca2+ induced by Aβ pores is expected also to interfere with neurotransmitters release [31,99,124].