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Aging and Disease    2015, Vol. 6 Issue (2) : 131-148     DOI: 10.14336/AD.2014.0423
Review Article |
The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease
Carolyn C. Rudy1,Holly C. Hunsberger1,Daniel S. Weitzner1,Miranda N. Reed1,2,3,*()
1Behavioral Neuroscience, Department of Psychology, West Virginia University, Morgantown, WV, 26506, USA
2Center for Neuroscience, West Virginia University, Morgantown, WV, 26506, USA
3Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV, 26506, USA
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Abstract  

Alzheimer’s disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity.

Keywords Beta-amyloid      tau      Alzheimer’s disease      excitotoxicity      glutamate      NMDA      astrocytes      tripartite synapse     
Corresponding Authors: Miranda N. Reed     E-mail: Miranda.Reed@mail.wvu.edu
Issue Date: 25 March 2015
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Carolyn C. Rudy
Holly C. Hunsberger
Daniel S. Weitzner
Miranda N. Reed
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Carolyn C. Rudy,Holly C. Hunsberger,Daniel S. Weitzner, et al. The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease[J]. A&D, 2015, 6(2): 131-148.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2014.0423     OR     http://www.aginganddisease.org/EN/Y2015/V6/I2/131
Figure 1.  The tripartite glutamate synapse. In the presynaptic neuron, glutamine (Gln) is converted to glutamate (Glu) by glutaminase and packaged into synaptic vesicles by the vesicular glutamate transporter (VGLUT). SNARE complex proteins mediate the fusion of vesicles with the presynaptic membrane. Astrocytes also release glutamate via the cystine-glutamate antiporter (Xc). Following release into the extracellular space, glutamate binds to presynaptic (mGluR2/3 and mGluR4/8), synaptic (S-NMDAR and AMPAR) and peri-/extra- synaptic (mGluR1/5 and E-NMDAR) glutamate receptors. Glutamate is cleared from the synaptic space through excitatory amino acid transporters (EAATs) on neighboring astrocytes (GLAST and GLT-1) and, to a lesser extent, on neurons (EAAT3). Glutamate is converted to glutamine by glutamine synthetase within the astrocyte before being transported to presynaptic neurons, thereby completing the glutamate-glutamine cycle.
mGluR GroupSubtypeGlutamate Receptor Affinity (EC50) [178]Location*Function*
Group ImGluR19Postsynaptic [179]Enhances excitability, synaptic plasticity, LTP/LTD [180, 181]
mGluR510Astrocytes [182]Elevates intracellular calcium [183, 184]
Group IImGluR24Presynaptic Inhibition of presynaptic glutamate [185]; LTD [186]
mGluR33Astrocytes [187]Inhibition of cystine/glutamate antiporter [26]
Group IIImGluR45Presynaptic [188] Inhibition of presynaptic glutamate [189]
mGluR71000Astrocytes [190]Increases glutamate uptake [187]
mGluR82.5 [191]
Table 1  Primary locations and functions of metabotropic glutamate receptors in the tripartite synapse.
Figure 2.  Aβ-mediated increases in extracellular glutamate and the resulting excitotoxicity. (1) Aβ increases presynaptic release of glutamate. (2) Aβ elevates astrocytic calcium via stimulation of astrocytic α7 nicotinic receptors, resulting in astrocytic glutamate release via an unknown mechanism. (3) Aβ decreases glutamate clearance from the synapse, thereby prolonging the duration of glutamate in the synapse and potentially resulting in the spread of glutamate to neighboring synapses. (4) Prolonged activation of S-NMDARs and AMPARs resulting from increased extracellular glutamate is predicted to cause desensitization and internalization of NMDA/AMPA, resulting in synaptic depression. (5) Glutamate spillover activates E-NMDARs, resulting in multiple deleterious downstream events, including an increase in tau kinase activity, cell death, and blockade of long-term potentiation (LTP) and CREB phosphorylation (pCREB).
Figure 3.  Tau-mediated excitotoxicity. (A) In healthy neurons, tau transports Fyn to the dendritic spine where Fyn, a tyrosine kinase that phosphorylates the NR2B receptor subunit Tyr1472, stabilizes the NR2B:PSD95 complex. (B) In the presence of Aβ and/or hyperphosphorylated tau (ptau), stabilization of the NR2B:PSD95 complex enhances glutamatergic excitotoxicity. (C) Removal of tau or Fyn prevents glutamatergic excitotoxicity mediated by Aβ.
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