Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Mota, Sandra I.; Ferreira, Ildete L.; Rego, A. Cristina

doi:10.1016/j.neuropharm.2013.08.013

Cited by 165 publications

(101 citation statements)

References 159 publications

(161 reference statements)

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“…A number of mechanisms have been proposed to explain how Ab(1-42) might block LTP, including endocytosis of synaptic NMDARs Goto et al, 2006;Kurup et al, 2010) and glutamate spillover resulting in overactivation of extrasynaptic NMDARs (O'Shea et al, 2008;Li et al, 2009), and in particular GluN2B-containing NMDARs (de Felice et al, 2007;Shankar et al, 2007;Ferreira et al, 2012;Li et al, 2011;Mota et al, 2014). Previous data from our laboratory indicate that both Ab(1-42) and monastrol result in reduced surface levels of NMDAR GluN1 and GluN2B subunits in cultured cells over several days, as measured by flow cytometry and confocal imaging (Ari et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

Freund¹,

Gibson²,

Potter³

et al. 2016

Mol Pharmacol

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Alzheimer's disease (AD) is characterized by neurofibrillary tangles, amyloid plaques, and neurodegeneration. However, this pathology is preceded by increased soluble amyloid beta (Ab) 1242 oligomers that interfere with the glutamatergic synaptic plasticity required for learning and memory, including N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). In particular, soluble Ab(1-42) acutely inhibits LTP and chronically causes synapse loss. Many mechanisms have been proposed for Ab-induced synaptic dysfunction, but we recently found that Ab(1-42) inhibits the microtubule motor protein Eg5/kinesin-5. Here we compared the impacts of Ab(1-42) and monastrol, a small-molecule Eg5 inhibitor, on LTP in hippocampal slices and synapse loss in neuronal cultures. Acute (20-minute) treatment with monastrol, like Ab, completely inhibited LTP at doses .100 nM. In addition, 1 nM Ab(1-42) or 50 nM monastrol inhibited LTP~5 0%, and when applied together caused complete LTP inhibition. At concentrations that impaired LTP, neither Ab(1-42) nor monastrol inhibited NMDAR synaptic responses until 60 minutes, when only~25% inhibition was seen for monastrol, indicating that NMDAR inhibition was not responsible for LTP inhibition by either agent when applied for only 20 minutes. Finally, 48 hours of treatment with either 0.5-1.0 mM Ab(1-42) or 1-5 mM monastrol reduced the dendritic spine/synapse density in hippocampal cultures up to a maximum of~40%, and when applied together at maximal concentrations, no additional spine loss resulted. Thus, monastrol can mimic and in some cases occlude the impact of Ab on LTP and synapse loss, suggesting that Ab induces acute and chronic synaptic dysfunction in part through inhibiting Eg5.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

Freund¹,

Gibson²,

Potter³

et al. 2016

Mol Pharmacol

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“…Considering the pharmacological effects observed here, the OST may serve as an assessment for investigating the interactive effects of cholinergic and glutamatergic signaling in animal models of schizophrenia (Dudchenko et al 2012). The OST also shows potential utility in the assessment of Alzheimer's disease and attention deficit, as it can characterize long-term and working memory, as well as assess performance across memory load (Lehohla et al 2004;Mota et al 2013). Therefore, the translational merits of the OST indicate it can be a useful measure for assessment of cognitive deficits across species and neurological disorders.…”

Section: Discussionmentioning

confidence: 99%

Influence of pharmacological manipulations of NMDA and cholinergic receptors on working versus reference memory in a dual component odor span task

et al. 2016

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Developed as a tool to assess working memory capacity in rodents, the odor span task (OST) has significant potential to advance drug discovery in animal models of psychiatric disorders. Prior investigations indicate OST performance is impaired by systemic administration of N-methyl-D-aspartate receptor (NMDA-r) antagonists and is sensitive to cholinergic manipulations. The present study sought to determine whether an impairment in OST performance can be produced by systemic administration of the competitive NMDA-r antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP; 3, 10, 17 mg/kg i.p.) in a unique dual-component variant of the OST, and whether this impairment is ameliorated by nicotine (0.75 mg/kg i.p.). Male Sprague-Dawley rats were trained to asymptotic level of performance on a 24-trial two-comparison incrementing nonmatching to sample OST. In addition, rats were administered a two-comparison olfactory reference memory (RM) task, which was integrated into the OST. The RM task provided an assessment of the effects of drug administration on global behavioral measures, long-term memory and motivation. Several measures of working memory (span, longest run, and accuracy) were dose dependently impaired by CPP without adversely affecting RM. Analysis of drug effects across trial blocks demonstrated a significant impairment of performance even at low memory loads, suggesting a CPP-induced deficit of olfactory short-term memory that is not load-dependent. Although nicotine did not ameliorate CPP-induced impairments in span or accuracy, it did block the impairment in longest run produced by the 10 mg/kg dose of CPP. Overall, our results indicate that performance in our 24 odor two-comparison OST is capacity dependent and that CPP impaired OST working, but not reference, memory.The odor span task, which was originally developed by Dudchenko et al. (2000), makes use of a primary sensory modality for rodents (olfaction) to assess the neurobiological and neuropharmacological basis of rodent memory. In the original procedure, rats were trained to dig in cups of sand, each mixed with a different household spice (e.g., basil or paprika), to retrieve buried food rewards. On each successive trial, a novel odor was presented, along with every odor that had been presented in preceding trials, but only responses to the novel odor were reinforced. To respond accurately on any given trial the rat needed to remember each stimulus it had encountered earlier in the session and withholds responses to these stimuli. Therefore, memory demands escalated over the course of the procedure as the number of odors the rat was required to remember increased. Dudchenko et al. (2000) demonstrated that performance in the task declined across trials, indicating that task accuracy was negatively impacted by increasing memory load. However, in this OST procedure, the number of comparisons presented on each successive trial increases in tandem with the number of stimuli to remember, confounding the relationship between accuracy and mem...

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“…Cdk5 involves in regulating every aspect of synaptic function, from neurotransmitter release, vesicle cycling, and ion channel modulation to protein clustering and synaptic structural change along with spine formation. Cdk5 regulates synaptic plasticity by directly phosphorylating numerous relevant substrates and interacting proteins, or may by indirectly disrupting Aβ generation [77,78].…”

Section: Cdk5 Modulates Synaptic Plasticitymentioning

confidence: 99%

The Role of Cdk5 in Alzheimer’s Disease

et al. 2015

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Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing β-amyloid (Aβ)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.

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Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Cited by 165 publications

References 159 publications

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

Influence of pharmacological manipulations of NMDA and cholinergic receptors on working versus reference memory in a dual component odor span task

The Role of Cdk5 in Alzheimer’s Disease

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