Early calcium dysregulation in Alzheimer's disease: Setting the stage for synaptic dysfunction

Department of Neuroscience, Rosalind Franklin University/the Chicago Medical School, North Chicago, IL 60064, USA.
Science China. Life sciences (Impact Factor: 1.69). 08/2011; 54(8):752-62. DOI: 10.1007/s11427-011-4205-7
Source: PubMed


Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease process. Amyloid plaques, neurofibrillary tangles and neuronal loss, though characteristic of AD, are late stage markers whose impact on the most devastating aspect of AD, namely memory loss and cognitive deficits, are still unclear. Recent studies demonstrate that structural and functional breakdown of synapses may be the underlying factor in AD-linked cognitive decline. One common element that presents with several features of AD is disrupted neuronal calcium signaling. Increased intracellular calcium levels are functionally linked to presenilin mutations, ApoE4 expression, amyloid plaques, tau tangles and synaptic dysfunction. In this review, we discuss the role of AD-linked calcium signaling alterations in neurons and how this may be linked to synaptic dysfunctions at both early and late stages of the disease.

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Available from: Shreaya Chakroborty
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    • "Studies of tau over-expressing neurons in culture have linked dendritic spine loss, the leading correlate to cognitive decline in AD [1,2,20], to alterations in calcium handling and mitochondrial mislocalization [12]. In addition, studies of Aβ toxicity have suggested that calcium dyshomeostasis precedes and leads to subsequent spine loss [8,9,14,16,38-42]. To determine whether calcium concentrations in the rTg4510 mice correlated with dendritic spine loss, spine density was calculated in rTg4510 and control mice and matched with the YC ratio of the parent dendrite in a subset of the dendrites imaged. "
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    ABSTRACT: Neurofibrillary tangles (NFTs) of tau are one of the defining hallmarks of Alzheimer's disease (AD), and are closely associated with neuronal degeneration. Although it has been suggested that calcium dysregulation is important to AD pathogenesis, few studies have probed the link between calcium homeostasis, synapse loss and pathological changes in tau. Here we test the hypothesis that pathological changes in tau are associated with changes in calcium by utilizing in vivo calcium imaging in adult rTg4510 mice that exhibit severe tau pathology due to over-expression of human mutant P301L tau. We observe prominent dendritic spine loss without disruptions in calcium homeostasis, indicating that tangles do not disrupt this fundamental feature of neuronal health, and that tau likely induces spine loss in a calcium-independent manner.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "Redistribution or mislocalization of PSD95, which serves as a scaffold for essential postsynaptic elements such as NMDA and AMPA receptors, may have negative ramifications for their localization or function as well (Hoover et al., 2010; Chakroborty and Stutzmann, 2011; D'Amelio et al., 2011; Huang and Mucke, 2012). Our data indicate a significant loss of PSD95, synapsin, and subunits NMDAR1 and GluR1 of NMDA and AMPA receptors, respectively, while NMDAR2A and GluR2 levels are "
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    ABSTRACT: Synapse loss, rather than the hallmark amyloid-β (Aβ) plaques or tau filled neurofibrillary tangles (NFT), is considered the most predictive pathological feature associated with cognitive status in the Alzheimer disease (AD) brain. The role of Aβ in synapse loss is well established, but despite data linking tau to synaptic function, the role of tau in synapse loss remains largely undetermined. Here we test the hypothesis that human mutant P301L tau over-expression in a mouse model (rTg4510) will lead to age-dependent synaptic loss and dysfunction. Using array tomography and two methods of quantification (automated, threshold-based counting and a manual stereology based technique) we demonstrate that overall synapse density is maintained in the neuropil, implicating synapse loss commensurate with the cortical atrophy known to occur in this model. Multi-photon in-vivo imaging reveals close to 30% loss of apical dendritic spines of individual pyramidal neurons suggesting these cells may be particularly vulnerable to tau-induced degeneration. Post-mortem, we confirm the presence of tau in dendritic spines of rTg4510-YFP mouse brain by array tomography. These data implicate tau-induced loss of a subset of synapses that may be accompanied by compensatory increases in other synaptic subtypes thereby preserving overall synapse density. Biochemical fractionation of synaptosomes from rTg4510 brain demonstrates a significant decrease in expression of several synaptic proteins, suggesting a functional deficit of remaining synapses in the rTg4510 brain. Together these data show morphological and biochemical synaptic consequences in response to tau over-expression in the rTg4510 mouse model. J. Comp. Neurol., 2012. © 2012 Wiley Periodicals, Inc.
    Full-text · Article · Apr 2013 · The Journal of Comparative Neurology
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    • "Considerable research has focused on the neurotoxicity of beta amyloid peptides (Ab) since they were identified in plaques from AD patients decades ago (Goate and Hardy, 2012; Holtzman et al., 2011; Selkoe, 1993), yet therapeutic studies targeting Ab have yielded disappointing or counterproductive results (Aisen et al., 2011; Galimberti and Scarpini, 2011; Karran et al., 2011; Selkoe, 2011b; Stone et al., 2011). Among other things, impediments to progress in this arena might reflect uncertainty regarding the relevant Ab species to target (Benilova et al., 2012), the use of inconsistent model systems or supraphysiologic Ab peptide concentrations (Castellani and Smith, 2011; Waters, 2010), incomplete understanding of physiologic versus pathologic roles of Ab and amyloid precursor protein (APP) (Chasseigneaux and Allinquant, 2012; Guo et al., 2012; Zhang et al., 2012), and incomplete consideration of alternative pathogenic mechanisms, particularly those affecting synapses (Chakroborty and Stutzmann, 2011). Because the mechanisms driving AD pathology appear disparate , effective therapeutic strategies might derive from a confluence of targets that are synergistic with, or alternative to, monopathic Ab-centric therapies. "
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    ABSTRACT: Alzheimer's disease (AD) is a multifactorial disorder of unknown etiology. Mechanistically, beta amyloid peptides (Aβ) and elevated Ca(2+) have been implicated as proximal and likely interactive features of the disease process. We tested the hypothesis that proximity to Aβ plaque might exacerbate activity-dependent neuronal Ca(2+) signaling in hippocampal pyramidal neurons from APP(SWE)/PS1(M146V) mice. Using combined approaches of whole cell patch clamp recording and 2-photon imaging of neuronal Ca(2+) signals with thioflavin-S plaque labeling in hippocampal slices, we found no correlation between thioflavin-S labeled Aβ plaque proximity and Ca(2+) responses triggered by ryanodine receptor (RyR) activation or action potentials in either dendrites or somata of AD mice, regardless of age. Baseline and RyR-stimulated spontaneous excitatory postsynaptic potentials also showed little difference in relation to Aβ plaque proximity. Consistent with previous studies, RyR-evoked Ca(2+) release in APP(SWE)/PS1(M146V) mice was greater than in nontransgenic controls. Within the soma, RyR-evoked Ca(2+) release was elevated in older APP(SWE)/PS1(M146V) mice compared with younger APP(SWE)/PS1(M146V) mice, but was still independent of plaque proximity. The results indicate that early Ca(2+) signaling disruptions can become yet more severe with age through mechanisms independent of Aβ plaques, suggesting that alternative pathogenic mechanisms might contribute to AD-associated dysfunction.
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