Dysregulation of Ca&lt;sup&gt;2+&lt;/sup&gt; Homeostasis in Alzheimer’s Disease: Role in Acetylcholinesterase Production and AMPA Receptor Internalization

Small, David H.

doi:10.1159/000333126

Cited by 7 publications

(5 citation statements)

References 56 publications

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“…With respect to AD, this has focused mainly on assessing the potential use of AMPAR modulators to boost cognitive performance with rather disappointing results to date [39]. However, AMPAR may also be a potentially important locus for the actions of Aβ within the synapse since Aβ interacts with and internalizes AMPAR [40]–[43], and disrupts GluA trafficking to the cell surface [44]. These interactions could then lead to deficits in AMPAR-evoked transmission [45] and loss of the molecular events that are central to synaptic plasticity and survival, similar to the aberrant Ca 2+ signaling, Akt and CREB phosphorylation that results from Aβ acting at NMDAR [46]–[48].…”

Section: Discussionmentioning

confidence: 99%

AMPA Receptor Activation Promotes Non-Amyloidogenic Amyloid Precursor Protein Processing and Suppresses Neuronal Amyloid-β Production

et al. 2013

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Soluble oligomeric amyloid β peptide (Aβ) generated from processing of the amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's Disease (AD) and through actions at glutamatergic synapses affects excitability and plasticity. The physiological control of APP processing is not fully understood but stimulation of synaptic NMDA receptors (NMDAR) can suppress Aβ levels through an ERK-dependent increase in α-secretase activity. AMPA-type glutamate receptors (AMPAR) couple to ERK phosphorylation independently of NMDAR activation raising the possibility that stimulation of AMPAR might similarly promote non-amyloidogenic APP processing. We have tested this hypothesis by investigating whether AMPAR directly regulate APP processing in cultured mouse cortical neurons, by analyzing APP C-terminal fragments (CTFs), soluble APP (sAPP), Aβ levels, and cleavage of an APP-GAL4 reporter protein. We report that direct stimulation of AMPAR increases non-amyloidogenic α-secretase-mediated APP processing and inhibits Aβ production. Processing was blocked by the matrix metalloproteinase inhibitor TAPI-1 but was only partially dependent on Ca2+ influx and ERK activity. AMPAR can therefore, be added to the repertoire of receptors that couple to non-amyloidogenic APP processing at glutamatergic synapses and thus pharmacological targeting of AMPAR could potentially influence the development and progression of Aβ pathology in AD.

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Section: Discussionmentioning

confidence: 99%

AMPA Receptor Activation Promotes Non-Amyloidogenic Amyloid Precursor Protein Processing and Suppresses Neuronal Amyloid-β Production

et al. 2013

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“…AbOs interact with complexes containing the GluA2 subunit of AMPA receptors, as suggested by co-immunoprecipitation and photoactivated amino acid cross-linking studies (Zhao et al 2010). Pharmacological inhibition or removal of surface AMPA receptors reduce AbO binding to neurons (Liu et al 2010;Zhao et al 2010;Small 2012). AbO binding and clustering at synapses also appear to require metabotropic glutamate receptors (mGluR5), as demonstrated by single particle tracking of quantum dot-labeled AbOs (Renner et al 2010).…”

Section: Abos Interact With a Multi-protein Receptor Complex That Incmentioning

confidence: 98%

“…; Zhao et al . ; Small ). AβO binding and clustering at synapses also appear to require metabotropic glutamate receptors (mGluR5), as demonstrated by single particle tracking of quantum dot‐labeled AβOs (Renner et al .…”

Section: Aβos Interact With a Multi‐protein Receptor Complex That Incmentioning

confidence: 99%

Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's disease

Paula-Lima

Brito-Moreira

Ferreira

2013

Journal of Neurochemistry

155

119

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Alzheimer′s disease (AD) is the most common form of dementia in the elderly. Memory loss in AD is increasingly attributed to soluble oligomers of the amyloid-b peptide (AbOs), toxins that accumulate in AD brains and target particular synapses. Glutamate receptors appear to be centrally involved in synaptic targeting by AbOs. Once bound to neurons, AbOs dysregulate the activity and reduce the surface expression of both N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) types of glutamate receptors, impairing signaling pathways involved in synaptic plasticity. In the extracellular milieu, AbOs promote accumulation of the excitatory amino acids, glutamate and D-serine. This leads to overactivation of glutamate receptors, triggering abnormal calcium signals with noxious impacts on neurons. Here, we review key findings linking AbOs to deregulated glutamate neurotransmission and implicating this as a primary mechanism of synapse failure in AD. We also discuss strategies to counteract the impact of AbOs on excitatory neurotransmission. In particular, we review evidence showing that inducing neuronal hyperpolarization via activation of inhibitory GABA A receptors prevents AbOinduced excitotoxicity, suggesting that this could comprise a possible therapeutic approach in AD.

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“…Aβ oligomers are believed to interact with complexes containing the glutamate alpha-2 (GluA2) subunit of AMPA receptors (AMPAR) based on co-immunoprecipitation and photoactivated amino acid cross-linking studies [274] as well as the observation that pharmacological inhibition and removal of surface AMPARs reduce Aβ binding to neurons [274–276]. Similarly, a mouse model of AD showed that the synaptic removal of AMPAR plays a key role in the Aβ-induced synaptic dysfunction [277].…”

Section: Amyloid Betamentioning

confidence: 99%

Amyloid-Beta and Phosphorylated Tau Accumulations Cause Abnormalities at Synapses of Alzheimer’s disease Neurons

Rajmohan

Reddy

2017

JAD

379

220

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Amyloid Beta (Aβ) and hyperphosphorylated tau are hallmark lesions of Alzheimer disease (AD). However, the loss of synapses and dysfunctions of neurotransmission are more directly tied to disease severity. The role of these lesions in the pathoetiological progression of the disease remains contested. Biochemical, cellular, molecular and pathological studies provided several lines of evidence and improved our understanding of how amyloid beta and hyperphosphorylated tau accumulation may directly harm synapses and alter neurotransmission. In-vitro evidence suggests that amyloid beta and hyperphosphorylated tau have both direct and indirect cytotoxic effects that affect neurotransmission, axonal transport, signaling cascades, organelle function, and immune response in ways that lead to synaptic loss and dysfunctions in neurotransmitter release. Observations in preclinical models and autopsy studies support these findings, suggesting that while the pathoetiology of positive lesions remains elusive, their removal may reduce disease severity and progression. The purpose of this article is to highlight the need for further investigation of the role of tau in disease progression and its interactions with Aβ and neurotransmitters alike.

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Dysregulation of Ca<sup>2+</sup> Homeostasis in Alzheimer’s Disease: Role in Acetylcholinesterase Production and AMPA Receptor Internalization

Cited by 7 publications

References 56 publications

AMPA Receptor Activation Promotes Non-Amyloidogenic Amyloid Precursor Protein Processing and Suppresses Neuronal Amyloid-β Production

AMPA Receptor Activation Promotes Non-Amyloidogenic Amyloid Precursor Protein Processing and Suppresses Neuronal Amyloid-β Production

Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's disease

Amyloid-Beta and Phosphorylated Tau Accumulations Cause Abnormalities at Synapses of Alzheimer’s disease Neurons

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