β-Amyloid Modulation of Synaptic Transmission and Plasticity

Venkitaramani, Deepa V.; Chin, Jeannie; Netzer, William J.; Gouras, Gunnar K.; Lesné, Sylvain; Malinow, Roberto; Lombroso, Paul J.

doi:10.1523/jneurosci.3478-07.2007

Cited by 105 publications

(80 citation statements)

References 79 publications

(89 reference statements)

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“…7). Thus, decreasing the level of NMDARs, suggested to be important for the interaction of A␤ with the neuronal membrane [21,31], might be facilitating its association to lipids previously not accessible, resulting in enhanced clustering (Figs. 2 and 3).…”

Section: Discussionmentioning

confidence: 99%

“…While some authors indicate that the co-immunoprecipitation of A␤ dodecameric oligomers with NR1 and NR2A is evidence for their interaction [31], others have failed to detect binding of A␤ to any known regulatory sites on glutamate receptors [28]. Furthermore, recent data indicates that such effects of A␤ on NMDA receptors may be due to its binding to postsynaptic anchoring proteins such as PSD-95 or other membrane proteins like prion [21,32,33].…”

Section: Introductionmentioning

confidence: 99%

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The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

Peters

Sepúlveda

Fernández-Pérez

et al. 2016

JAD

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Abstract. Alzheimer's disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-␤ peptide (A␤) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with A␤ affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by A␤ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA approaches, increased the association of A␤ to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and A␤. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because A␤ was now unable to cause membrane perforation, suggesting a complex relationship between A␤ and NMDARs. Because previous studies have recognized that A␤ oligomers are able to increase membrane permeability and produce amyloid pores, the present study supports the conclusion that NMDARs play a critical protective role on A␤ actions in hippocampal neurons. These results could explain the lack of correlation between brain A␤ burden and clinically observed dementia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

Peters

Sepúlveda

Fernández-Pérez

et al. 2016

JAD

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“…These studies reported that the type of LTP disrupted in AD model synapses is NMDAR-dependent (Shankar et al, 2007;Snyder et al, 2005). In addition, it has been well documented that Aβ-mediated synaptic depression shares signaling pathways with NMDAR-dependent LTD, including major players such as calcineurin, a calcium-activated phosphatase, and caspase-3 (Hsieh et al, 2006;Venkitaramani et al, 2007). Moreover, some reports suggest that blockade of NMDAR alleviates Aβ-mediated synaptic depression, suggesting NMDAR as a potential drug target (Shankar et al, 2007).…”

Section: Clinical Implications Of "Metabotropic" Nmdarsmentioning

confidence: 98%

“…Aβ is known to exert detrimental effects at the synaptic level before the onset of behavioral symptoms such as memory loss and cognition deficits (Venkitaramani et al, 2007). It has been reported that preparations obtained from a number of animal models of AD exhibit impaired LTP, thereby recapitulating cognitive dysfunction observed in patients with AD (Shankar et al, 2008;Snyder et al, 2005;Walsh et al, 2002).…”

Section: Clinical Implications Of "Metabotropic" Nmdarsmentioning

confidence: 99%

NMDA Receptor as a Newly Identified Member of the Metabotropic Glutamate Receptor Family: Clinical Implications for Neurodegenerative Diseases

Chung

2013

Molecules and Cells

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“…Ab is a 40-42 amino acid peptide implicated in synaptic dysfunction and cell death in Alzheimer's disease (AD; Lue et al, 1999;Venkitaramani et al, 2007). The interest in the role of Ab after TBI has grown from epidemiological studies that have demonstrated an association between a history of TBI and the development of AD later in life (Graves et al, 1990;Mortimer et al, 1985Mortimer et al, , 1991Salib and Hillier, 1997;Szczygielski et al, 2005;Van Den Heuvel et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Detrimental Effect of Genetic Inhibition of B-Site App-Cleaving Enzyme 1 on Functional Outcome after Controlled Cortical Impact in Young Adult Mice

Mannix

Zhang

Park

et al. 2011

Journal of Neurotrauma

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Abstractb-Amyloid (Ab) peptides, most notably associated with Alzheimer's disease, have been implicated in the pathogenesis of secondary injury after traumatic brain injury (TBI). A prior study has demonstrated that blocking the b-site amyloid precursor protein (APP)-cleaving enzyme 1 (Bace1) required for production of Ab from APP improved functional and histologic outcomes after controlled cortical impact (CCI) in aged mice. However, the majority of patients with severe TBI are young adults under the age of 40. Prior experimental models have suggested age-dependent differences in Ab clearance, and a recent study in our lab suggests that young animals remediate acute elevations in Ab after CCI better than older animals. We therefore tested the hypothesis that Bace1 deletion in young adult mice would not be protective after CCI. Male Bace1 knockout (Bace1 -/-) and wild-type Bace1 +/+ (C57BL/6) mice (2-3 months old) were subjected to CCI (n = 18-23/group) or sham injury (n = 10-12/group). Functional outcomes were assessed with wire grip (motor) and the Morris water maze (MWM; spatial memory). Soluble Ab levels were assessed at 48 h after CCI. Histopathological outcomes were assessed by lesion and hippocampal volume. Clustered ordinal logistic regression showed overall significant impairment in motor performance in injured Bace1-/-versus Bace1 +/+ animals ( p = 0.003). No significant differences in MWM performance were found on repeated-measures ANOVA ( p = 0.11) between groups. Probe scores were significantly worse in injured Bace1-/-versus Bace1 +/+ mice ( p = 0.0009). Soluble Ab 40 was significantly lower in ipsilateral hemispheres of Bace1 -/-than in Bace1 +/+ animals after CCI (0.9 [IQR 0.88-0.94] pmol/g protein versus 3.8 [IQR 2.4-6.0] pmol/g protein; p = 0.005). Lesion and hippocampal volumes did not differ between injured groups. The data suggest that therapies targeting Bace1 may need to be tailored according to age and injury severity, as their use may exacerbate functional deficits after TBI in younger or less severely injured patients.

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β-Amyloid Modulation of Synaptic Transmission and Plasticity

Cited by 105 publications

References 79 publications

The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

NMDA Receptor as a Newly Identified Member of the Metabotropic Glutamate Receptor Family: Clinical Implications for Neurodegenerative Diseases

Detrimental Effect of Genetic Inhibition of B-Site App-Cleaving Enzyme 1 on Functional Outcome after Controlled Cortical Impact in Young Adult Mice

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