The first and the best characterized mechanism of receptor d

The first and the best-characterized mechanism of receptor-dependent internalization of Aβ is mediated via the α7-nicotinic molarity by dilution receptor [82]. Lipoprotein receptor protein represents the second best-studied route that facilitates the uptake of Aβ by neurons, involving additional molecules such as apolipoprotein E (APOE) [16]. In basal forebrain cholinergic neurons, p75NTR can mediate the uptake of Aβ [90,93,94]. Finally, Aβ has been shown to bind multiple scavenger receptors and advanced glycation end products in neurons and glia [29,115] as well as formyl peptide receptor-like-1 expressed in the brain [49]. As both, membrane turnover and receptor internalization are tightly coupled with SVC at axon terminals, presynaptic compartments present the primary site for Aβ entry into neurons. These processes not only can enrich the intracellular membrane-bound organelles with Aβ but are thought also to favor the buildup of Aβ in the cytoplasm, with cytotoxic effects [148,150]. It is noteworthy that the extent of Aβ internalization can be influenced by specific mutations, with especially high intracellular Aβ deposits detected in the brains affected by Swedish Mutation of APP (K595M and M596L) [18,111]. Analysis of the intracellular Aβ distribution in SH-SY5Y neuroblastoma cells revealed that monomers of both Aβ40 and Aβ42 can colocalize with markers for RAB-8 (trans-golgi network and golgi), RAB-9 (trans-golgi network and recycling endosomes), lysosome-associated membrane glycoproteins 1/2 (late endosomes and lysosomes), RAB-5 (early endosomes), RAB-3 (exocytosis vesicle marker), and vesicle associated membrane protein (VAMP)-2 (synaptic vesicles). Importantly, however, a substantial fraction of Aβ42 granules do not colocalize with any of these, implying cytoplasmic Aβ aggregates [150]. Using high-power electron microscopy, it was shown recently that a large fraction of intracellular Aβ is present in the cytosol [150]. While cellular mechanisms leading to deposition of Aβ therein remain a matter of controversy, the leakage of Aβ from membrane-bound compartments and active export from the endoplasmic reticulum to the cytoplasm for degradation through the endoplasmic reticulum–associated protein degradation pathway have been closely considered [69]. It appears that under physiological conditions, only limited amounts of Aβ are transported into the cytoplasm and timely degraded therein. If dysregulated, this process leads to excessive depositions of cytoplasmic Aβ, which interferes with a range of proteins, including the proteasome complex [3,88] and SVC proteins at presynaptic terminals. Analysis of the functional consequences of intracellular Aβ for synaptic functions in the human brain is limited to correlational studies in postmortem tissue. Experimental data from animal models and neuronal cultures, however, show manifold effects of intracellular Aβ with a direct and indirect impact on the neurotransmitter release machinery. Within endosomes, Aβ leads to disruption of endosomal sorting via inhibition of the ubiquitin-proteome system [3]. This mechanism has been discussed particularly in the context of the buildup of tau protein and its abnormal distribution, critical for synaptic functions [87,136]. As noted, proteasome inhibition also accelerates the accumulation of intracellular Aβ, with detrimental effects on the molecular machinery of neurotransmitter release [79,145]. Intracellular Aβ interferes with presynaptic functions also via disruption of mitochondrial biology, depleting presynaptic and axonal mitochondria and changing their size and number [150]. Finally, presynaptic Aβ has been shown to interfere with molecular scaffolds governing the trafficking of synaptic vesicles and their priming for regulated exocytosis [112,144]. While the exact mechanisms underlying these abnormalities remain unclear, the clues gained from recent studies in this direction highlight a considerable variety of mechanisms and functional outcomes.