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resulting in reduced secretion of tumor necrosis Neuroexcitotoxicity
factor‑alpha, NO, and interleukin‑1 beta in LPS‑treated Glutamate excitotoxicity has been hypothesized to have
BV2 cells, a murine microglia cell line. Furthermore, a role in AD pathogenesis. Dysfunction of glutamate
[34]
donepezil may inhibit neuronal death and cognitive decline transporters has been implicated in this pathway. [50] It
by repressing oligomeric Aβ‑triggered inflammatory has been reported that hippocampal excitatory amino
pathways in microglia. [35] Thus, donepezil‑mediated acid transporter 1 (EAAT1) and EAAT2 expression is
attenuation of the release of inflammatory mediators significantly reduced in AD, [49] further reinforcing the
may result from inhibition of protein expression of notion of a deficit in glutamate clearance in AD brain.
proinflammatory molecules. In addition to uptake defects, the abnormal release of
glutamate from vesicle stores has been implicated as
The cholinergic pathway has been shown to exert a source of excess extracellular glutamate in AD. [51]
anti‑inflammatory effects on several diseases such Excessive activation of glutamate receptors leads
as rheumatoid arthritis, [36] inflammatory bowel to a number of deleterious consequences including
disease, [37] sepsis, [38] and cardiovascular diseases. [39] impairment of calcium buffering, generation of
On the other hand, nAChR has been shown to possess free radicals, and activation of the mitochondrial
anti‑inflammatory properties in macrophages, [40] and permeability transition that results in release of
the activation of α7‑nAChR significantly inhibits apoptogenic proteins into the cytosol, where they
the production of proinflammatory cytokines. [41] It trigger caspase‑dependent apoptosis or promote
has been demonstrated that AChEI treatment may autophagy. [52]
favor a Th2‑mediated immune response by activating
B‑lymphocytes and increasing immunoglobulin We and others have demonstrated that Aβ inhibits
production. [42] Galantamine‑enhanced microglial Aβ glutamate uptake in rat cortical synaptosomes, cultured
[9]
phagocytosis to promote Aβ clearance requires the cells, and acute brain slices. These findings are
combined action of an ACh competitive agonist and also consistent with an intracerebroventricular
the allosterically potentiating ligand for nAChRs. [43] injection of Aβ into rat brain, which causes a rapid
Furthermore, plasma anti‑Aβ antibody levels in AD increase in interstitial fluid glutamate levels without
1‑42
patients were found to be significantly increased after altering gamma‑aminobutyric acid or aspartate. [53] The
AChEI treatment, [44] thus suggesting that increasing the hydrophobic Aβ oligomers may bind principally to
endogenous response against Aβ might provide new membrane lipids, and thereby, secondarily interrupt
insights for AD therapy. Recently, several promising the structure and function of synaptic transmembrane
studies have been conducted in phase II and phase transporters (glutamate transporters), leading to
III trials using active and passive immunotherapies, increases in extracellular glutamate concentration.
respectively. [45]
Activation of extrasynaptic receptors
GLUTAMATERGIC SYSTEM Electron microscopic studies have shown that most
plasmalemma receptors are extrasynaptically located,
Glutamate is one of the most prominent whereas only 1‑2% of cell membrane receptors are
neurotransmitters in the body. It is present in over 50% located at synaptic sites in the hippocampus. [54] Thus,
of the nervous tissue. [46] It plays a prominent role the chemicals distribute in the extracellular fluid
in a variety of brain functions including synaptic and bind preferentially to these vastly extrasynaptic
transmission, neuronal growth and differentiation, receptors. Extrasynaptic NMDARs, that is, receptors
synaptic plasticity, learning and memory, and other that are not activated during low‑frequency synaptic
cognitive functions. events, can be found at various locations, such as
the cell body, the dendritic shaft, the neck of the
The role of the glutamatergic system is to convert dendritic spine, and adjacent to the postsynaptic
nerve impulses into a chemical stimulus by controlling density. It has been found that synaptic NMDAR
the concentration of glutamate at the synapse. It is activity is extremely important for neuronal survival,
well‑accepted that LTP induction triggers the NMDAR, whereas the extrasynaptic NMDARs are coupled
and therefore, activates the AMPA receptor in the CA1 to cell death pathways. [55] Using both whole‑cell
region. [47,48] NMDAR activation allows Ca to enter recording and Fluo‑4 calcium measurements, we
2+
the postsynaptic cell, which subsequently triggers confirmed that Aβ rapidly and significantly increases
a number of kinase pathways and increases protein extrasynaptic NMDA responses. Soluble Aβ oligomers
transcription. This process strengthens synapses activate extrasynaptic NR2B‑containing NMDARs,
and increases synaptic density, thus allowing fast thus increasing downstream calpain signaling and
adaptations of network activity which are critical for p38 mitogen‑activated protein kinase activity.
[9]
information processing. [49] Several studies have demonstrated that selective

276 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 277