Detailed analysis of the dose dependence of A effects reveal

Detailed analysis of the dose dependence of Aβ effects revealed that at low amounts, Aβ can also act as a positive regulator of presynaptic activity, enhancing the neurotransmitter release probability and increasing the neuronal excitability [2]. The facilitator effects of low Aβ dose on excitatory transmission does not involve postsynaptic N-methyl-D-aspartate receptor and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor currents, but has shown dependence on activation of α7–nicotinic L-α-Aminoadipic Acid australia receptor, in agreement with the presynaptic action site [81,103,104]. From these studies, it emerges that the directionality of Aβ effects in addition to the dose also depends on the site of action. While in the first instance, the presynaptic modulator effects of exogenous Aβ42 on transmitter release were thought to be mediated only via stimulation of presynaptic α7–nicotinic acetylcholine receptor and downstream changes in the presynaptic calcium [32,139], other mechanisms underlying the presynaptic effects have been subsequently also considered. In terms of the action mode, it is important to note that both local autocrine and long-range paracrine action of Aβ on synaptic transmission have been documented, with potent effects on the strength of synaptic transmission and on the density of synaptic connections described [52,135,139] (Fig. 1A and B). Soluble Aβ is present in the healthy brain, with its physiological levels in rodents estimated to be within the picomolar range [104,117]. In healthy humans, the concentrations of Aβ40 and Aβ42 in the cerebrospinal fluid are ∼1.5 and ∼2.0 nM, respectively [38]. It is noteworthy that while the level of Aβ in the cerebrospinal fluid of preclinical AD exceeds that of physiological, with the emergence of amyloid plaques and a cognitive deficit of clinical AD, the concentration of Aβ in the cerebrospinal fluid declines [14,38,140]. The impact of such slow changes in endogenous Aβ levels on synaptic transmission in the human brain remains to be shown. Evidence from amyloid precursor protein (APP)–knock-out (KO) [118], presinilin-1 (PS1)–KO [116], or β-secretase-1 (BACE1)–KO mice [68] lacking endogenous Aβ shows that both synaptic transmission and plasticity are notably reduced. Likewise, pharmacological inhibition of BACE1 caused a reduction in dendritic spine formation and synaptic plasticity in the cerebral cortex and hippocampus [36]. These findings agree with the positive effects of thiorphan (inhibitor of Aβ degradation) on the frequency of miniature excitatory postsynaptic current in mouse brain slices [2] (Fig. 1C and D). While in all these reports, the presynaptic effects of Aβ are viewed as a result of activation of surface receptors, the direct influence of intracellular Aβ42 oligomers injected into axon terminals, causing a blockade of synaptic transmission, has also been also documented [79] (Fig. 1E and F). Unchanged presynaptic Ca2+ currents and reduction in the size of the docked synaptic vesicle pool imply direct negative effects of intracellular Aβ on the SVC. As discussed in the following sections, behind these effects underlie Aβ action upon all major steps of the SVC, from postfusion membrane recovery to synaptic vesicle trafficking, docking, priming, and regulated fusion of vesicles at the active zone.
Reaching and wrecking synapses from within Although most intracellular Aβ is contained within membranous compartments, substantial amounts have also been found in the cytoplasm of neurons [13,42]. The first evidence for intracellular Aβ came shortly after the discovery of Aβ as the main constituent of AD plaques. However, as early studies used anti-Aβ antibodies with cross-reactivity with APP, the validity of conclusions drawn remained a matter of controversy [66]. Interestingly, in autopsy samples tested from individuals between 38 and 83 years of age, Aβ deposition in neurons proved to be age-independent [66]. It is important to note that unlike the bulk of extracellular Aβ terminating at AA40, most intracellular Aβ terminates at AA42 [40,42,130]. There seems to be a close mechanistic link between extracellular and intracellular pools of Aβ, with deposition of extracellular Aβ in plaques causing a reduction of intracellular Aβ [64,85]. From the clinical standpoint, it is important to note that increases in intracellular Aβ can be detected from early, mild cognitive impairment stages of AD, with its levels particularly high in neurons of the hippocampus and entorhinal cortex, two brain regions affected most severely by AD [40,130]. Whether the buildup of intracellular Aβ in diseased brains results from reduced secretion or enhanced reuptake of extracellular Aβ remains to be determined. It is clear, however, that pathological loading of neurons with Aβ occurs primarily when the levels of extracellular soluble Aβ are abnormally high and depends on its specific binding to a range of receptor proteins and membrane biomolecules (e.g., lipids and proteoglycans).