br Acknowledgments and Disclosures br

Acknowledgments and Disclosures
Alzheimer's disease as a synaptic pathology Alzheimer's disease (AD) is a chronic neurodegenerative Amyloid β-peptide (10-35), amide receptor disorder and the most common cause of dementia in the elderly. Progressive depositions of amyloid plaques and neurofibrillary tangles together with degeneration of neurons and synapses in selected brain areas are the most recognized histopathological features of the disease. From histochemical and functional studies, it emerges that the extent of synaptic loss in AD correlates closely with cognitive decline and memory deficit, with dysregulations of neuronal calcium and subtle impairments in synaptic function detectable from early preclinical stages, before the emergence of plaques and neurofibrillary tangles [4,5,60,133]. In the cerebral cortex, a 25%–35% decrease in synaptic connections has been reported within the first 2–3 years of clinical AD, while in the hippocampus these numbers exceed 50% [5,28]. Elucidating the mechanisms of synaptic impairments, thus, are of special interest for a better understanding of AD pathobiology and early therapeutic intervention, before slowing down the onset of irreparable damage with synaptic loss and cognitive decline [27,46]. According to the amyloid hypothesis of AD [45,47], synaptic impairments are triggered by a pathological increase in the amyloid β (Aβ) level in the brain, with soluble oligomers of Aβ42 known to be especially detrimental. Among the best-characterized negative effects of Aβ, the dysregulation of Ca2+ homeostasis and disruption of the fine balance between a wide range of kinases and phosphatases are of special relevance to the synaptic deficit and altered neuronal excitability [8,12,43]. Most reports of the synaptic effects of Aβ have been focusing on the postsynaptic side, with impairments of N-methyl-D-aspartate [126], metabotropic glutamate receptor 5 [109], and M1 muscarinic cholinergic [37] receptors as well as deregulation of insulin and insulin growth factors [77], ephrin [24] and neurotrophin signaling [26,90]. The stimulation of Fyn kinase downstream of N-methyl-D-aspartate receptor and prion protein activation appears to hold centre stage in the postsynaptic toxicity of Aβ, causing collapse of dendritic spines and synaptic degeneration [21,137]. Misplacement of microtubule-associated tau protein from axon to dendrites also contributes toward postsynaptic deficits with loss of dendritic spines, leading to degeneration of synaptic connections [50,149]. Reports also suggest a key role for glycogen synthase kinase 3β, cyclin-dependent kinase 5 (CDK5), and other kinases in postsynaptic pathology of AD [25,86,114]. The presynaptic facets of AD, in the meantime, remain poorly elucidated, despite mounting evidence implying axon terminals as the prime site for Aβ production and the starting point of synaptic pathology [89,120]. Results of human and animal AD model studies demonstrate considerable changes in the expression and functions of presynaptic proteins, attributed in parts to direct effects of Aβ on the synaptic vesicle cycle (SVC) (Box 1). In this study, we present a detailed account of Aβ interference with different stages of SVC and transmitter release. Discussed herein, Aβ-related changes in presynaptic biology suggest a considerable overlap between the physiological and pathological effects of Aβ, unveiling numerous previously unrecognized challenges and therapeutic opportunities.
Modulation of presynaptic functions by Aβ Discovery of the positive correlation between the cognitive decline and synaptic loss associated with AD [30,133] prompted penetrating research into the effects of Aβ on synaptic mechanisms [97,101]. Until recently, the general consensus was that at high dose, both, natural and synthetic Aβ oligomers suppress synaptic transmission and plasticity [39,71,121,122]. These effects mostly induced under experimental settings by application of exogenous Aβ have been ascribed in part to disruption of SVC and related changes in presynaptic release [57,59]. In extreme cases, over 50% reduction in the frequency of miniature excitatory postsynaptic currents has been observed in brain slices upon acute exposure to Aβ oligomers, implying a potent presynaptic site of action [121]. More recently, the focus has shifted on the effects of endogenous Aβ, with several reports demonstrating that both, the production and secretion of Aβ into the extracellular space is tightly controlled by neuronal activity (Box 1). Within the intact brain, strong association between Aβ secretion and synaptic functions has been observed during pathological events, such as epileptiform activity induced by electrical stimulation [23] and under certain type of physiological activity of brain circuits [53]. Such effects of Aβ were considered as part of a feedback loop that controls local and global neuronal excitability and circuit dynamics.