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Synaptic loss is one of the pathological hallmarks of AD the nAChR, facilitating LTP induction. [21] Selective
and the best correlate of cognitive decline [10,11] suggesting depletion of medial septum cholinergic neurons caused
that it is a critical event in the pathophysiology of LTP impairment and glutamatergic synaptic current
the disease. Several factors such as Aβ production, alteration in the hippocampus. [22]
cholinergic dysfunction, NFT accumulation,
inflammatory agents, oxidative stress, mitochondrial Glutamatergic effect
dysfunction, glutamate‑mediated excitotoxicity, and The facilitation of LTP by mAChR activation is thought
genetic components are reported to be involved in to be mediated by enhancement of synaptic NMDAR
[14]
[3]
the pathogenesis. Proposed explanations for the activity either by direct alteration of NMDAR channels
2+
pathophysiology of AD include the cholinergic or by induction of Ca release from endoplasmic
hypothesis, [11] the soluble Aβ oligomers hypothesis, [12] reticulum stores. [23] The mAChRs also inhibit a variety
and the tau hypothesis. [12,13] of potassium channels including small conductance
calcium‑activated KCa2 channels (SK channels). [24]
CHOLINERGIC SYSTEM Therefore, mAChR activation might induce a parallel
long‑term enhancement of both α‑amino‑3‑hydrox
Acetylcholine (ACh) is widely distributed in the nervous y‑5‑methyl‑4‑isoxazolepropionic acid (AMPA) and
system and plays a critical role in cerebral cortical NMDAR‑mediated transmission. [25]
development, cortical activity, and learning and memory
processes. Cholinergic neurons in the brainstem and It has been reported that chronic nicotine administration
basal forebrain project axons to many areas of the brain. and in vitro acute nicotine treatment increases ACh
All functions of the cholinergic system are controlled release and enhances NMDAR responses in the
by the interaction of ACh with two families of receptors: hippocampus. [26] One potential mechanism is that
muscarinic ACh receptors (mAChRs) and nicotinic ACh nicotine acts at presynaptic nAChRs to increase
receptors (nAChRs). [14] glutamate release onto postsynaptic NMDARs. [27]
The activation of nAChRs causes Ca entry through
2+
Hippocampal cholinergic activity contributes to memory receptor channels, which can trigger Ca release
2+
Many studies have shown that hippocampal‑dependent from intracellular stores. [28] Multiple lines of evidence
learning is associated with an increase in hippocampal also suggest that nicotine could act to ameliorate
ACh levels; thus, the elevation of extracellular hippocampal‑based learning deficits associated with
ACh is thought to reflect hippocampal‑dependent changes in NMDAR function. [29] Consistent with these
memory processes. [15] Several behavioral studies studies, pretreatment with AChE inhibitors has been
have demonstrated that lesion‑induced damage to found to protect cortical neurons from glutamate
cholinergic activity in the basal forebrain and its neurotoxicity in a time‑ and dose‑dependent manner
projections to the neocortex induced learning and through activation of nAChR. [30]
memory deficits. [16] Pharmacological experiments have
further confirmed that cholinergic receptor agonists Anti‑inflammatory effect
and acetylcholinesterase inhibitors (AChEIs) reduce The deposition of Aβ is the result of an imbalance
the severity of cognitive dysfunction, [17] whereas between Aβ production and clearance. This imbalance
anticholinergic drugs cause learning and memory leads to a situation of chronic inflammation in the
deficits in both animal and humans. [18] Antagonists of brain. Aβ deposition contributes to the activation of
mAChRs such as scopolamine, impair the encoding astrocytes and microglia, and induces the production
of new memories in animal models of learning of a series of proinflammatory cytokines, chemokines,
and memory and produce cognitive impairment in macrophage inflammatory proteins, leukotrienes,
humans. [15] reactive oxygen species, and nitric oxide (NO). [3,31,32]
The neuroinflammatory cytokines may not only
It has been found that pharmacological activation of contribute to neuronal death, but they might also
mAChRs or nAChRs produces an LTP‑like increase influence classical neurodegenerative pathways such
in synaptic transmission in the hippocampal CA1 as amyloid precursor protein (APP) processing and tau
region. Blockade of the presynaptic inhibitory M2/M4 phosphorylation.
[14]
subtype of mAChRs by methoctramine increased ACh
levels, and elicited a pharmacological LTP that shares A growing body of studies using donepezil has
[19]
a similar mechanism with tetanus‑induced LTP. [20] In shown that donepezil does not function solely at the
accordance, both the endogenous release of ACh in vivo level of ACh, but also has potent anti‑inflammatory
and the exogenous application of mAChR agonists effects in AD patients, a tauopathy mouse model and
in vitro facilitate the induction of LTP. [14] Increasing lipopolysaccharide (LPS)‑treated animals. Donepezil
[33]
endogenously released ACh specifically activates inhibits proinflammatory gene expression directly

274 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 275