PubMed: 25514383

Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment.
Maskos U | Lombardo S

Evidence 71933623d8

Akt phosphorylation mediates the downstream activation of an antiapoptotic pathway, which is also activated by nicotine treatment (Kihara et al., 2001)

Evidence 92db9c82a3

As a consequence of the lower Abeta concentration, the plaque load was clearly reduced in APP-alpha7KO mice

Evidence 0a47b12c9f

Cotinine is a nicotine metabolite known for its positive effects on memory and attention and lower toxicity compared to nicotine (Hatsukami et al., 1997)

Evidence 935bf267f0

In a mouse model of AD, cotinine treatment decreased the plaque load and was able to activate the Akt pathway, that was shown to be neuroprotective (Echeverria et al., 2011)

Evidence 9eb8a6493d

Cotinine is an alpha7 nAChR PAM (positive allosteric modulator)

Evidence 4fb59e2e77

Experiments performed on X. laevis oocytes transiently transfected with alpha7 or alpha4beta2 cDNA showed a concentration dependent effect of Abeta on receptor inhibition. In this case the peptide used was Abeta1-40 and the concentrations adopted were between 0.1 and 10 mM, with increased Abeta concentration resulting in a bigger inhibition of the receptor (Tozaki et al., 2002)

Evidence 5b48cd588c

Modulation of nAChRs by Abeta was also found in ex vivo studies: Pettit and colleagues (2001) used rat hippocampal slices to show that Abeta1-42 incubation is able to reduce postsynaptic currents and open probability of both alpha7 and non-alpha7 nAChRs subtypes, demonstrating an interaction between Abeta and other nAChR subunits

Evidence 8d6868ba8c

They demonstrated that Abeta1-42 drives a reversible inhibition of nAChR-mediated currents in hippocampal GABAergic neurons recorded from rat slices. In these experimental conditions the most effective Abeta1-42 concentration was 500 nM, but inhibition was found also at the lower concentration of 100 nM

Evidence c5eac4798b

With the use of selective antagonists it was possible to determine that inhibition operates on both alpha7 and non-alpha7 receptors (Pettit et al., 2001)

Evidence d2814f2258

The incubation of cultured rat hippocampal neurons with Abeta1-42 resulted in inhibition of alpha7 nAChRs, more precisely of both somato-dendritic and presynaptic populations of receptors

Evidence 9117c333c9

Further studies showed an inhibitory effect of Abeta1-42 on human alpha4beta2 nAChRs transfected in the cell line (SHEP1) (Wu et al., 2004)

Evidence 91501f175b

Subsequent to incubation with pM concentrations of Abeta1-42 monomers and oligomers, an increase of hippocampal LTP was observed

Evidence fab6607be7

Later it was shown that Abeta is able to activate also beta2*-nAChRs (beta2 subunit-containing nAChRs)

Evidence 95fdb332e0

This class of receptors seems to be particularly sensitive to Abeta-induced toxicity (Khiroug et al., 2002; Liu et al.,2009, 2012)

Evidence 61444f3812

It was then postulated that Abeta-nAChR interaction has a physiological role in neuronal homeostasis that is disrupted when Abeta concentrations increase in a pathological context, leading to receptor inhibition and possible cellular toxicity (Dineley et al., 2001; Parri et al., 2011)

Evidence 7973443bdb

A different set of experiments demonstrated that Abeta enhances ACh activation of the alpha4beta2 nAChRs expressed in oocytes, this first activation of the receptor was followed by its inhibition (Pym et al., 2005)

Evidence e350683866

However, alpha7 nAChR activation was observed in X. laevis oocytes when a range of Abeta concentration spanning from 1 to 100 pM was applied (Dineley et al., 2002)

Evidence eff814f790

In this system enhancement of Akt phosphorylation and activation of ERK pathway was observed following alpha7 agonist treatment, suggesting that Abeta inhibits the neuroprotective effect of alpha7 nAChR activation (Zhi et al., 2014)

Evidence b5a676a9f9

An in vivo Abeta infusion in mice was able to enhance hippocampal dependent memory, highlighted with memory tasks such as the Morris water maze and contextual fear conditioning, which are both hippocampus dependent behavioural tasks (Puzzo et al.,2008)

Evidence 3dc08eca45

With the progression of the disease the amount of Abeta increases, it starts to accumulate, and becomes toxic for the neurons (Hernandez et al., 2010)

Evidence 3324597404

The explanation proposed by the authors is that alpha7 nAChR activation through nicotine binding could promote survival pathways and recover the synaptic damage caused by Abeta (Inestrosa et al., 2013)

Evidence 088749dc6d

Pregnenolone sulfate (PREGS) is an endogenous steroid known to ameliorate cognitive performance in animals. PREGS is a modulator of synaptic plasticity, acting on the activation of glutamatergic transmission (Smith et al., 2014)

Evidence 309d3a0497

The treatment improved spatial memory and reduced apoptosis in CA1 pyramidal cells

Evidence 3a5ad6e9ac

Woolf (1998) proposed a model in which acetylcholine (ACh) release leads to the modulation of cortical circuitry that finally encodes for storage of long-term memory

Evidence c330702a13

Aged beta2 null mutant mice have a thinner cortex compared to agematched wild-type controls (Zoli et al., 1999). This work should be pursued further as it indicates a “neurotrophic” action of beta2 receptor activation by endogenous ACh (Zanardi et al., 2007)

Evidence 2b17c70c7d

Methyllycaconitine (MLA), an alpha7 nAChR antagonist, showed neuroprotective effect on mouse and rat primary cell culture (Martin et al., 2004)

Evidence 4fd664055a

The analysis of the Abeta fraction reduced by nicotine showed that mainly insoluble Ab1-40/42 was affected while there was no change in soluble Abeta (Nordberg et al., 2002)

Evidence 78b6efe79e

The short-term treatment of 10 days showed a significant reduction in cortical insoluble Abeta1-40/42

Evidence 0d4db1aff3

Long-term nicotine administration elicited a reduction in Abeta deposits in blood vessel

Evidence 13f66f2be6

APPSwe mice at 14.5 months have fewer alphaBungarotoxin binding sites, while in transgenic mice treated with nicotine the number of alphaBungarotoxin binding sites was recovered and comparable to non transgenic age-matched control mice, suggesting that there was an increase in the population of alpha7 nAChRs (Hellstrom-Lindahl et al., 2004)

Evidence 6770de020d

Nicotine treatment improved the memory deficit, highlighted with the Morris water maze task. Surprisingly, this study showed a dose dependent increase of alpha7 nAChR, a result that is in contrast with the literature (Oddo et al., 2005)

Evidence d3d5b5729c

Mice aged 6 months were treated for one month with nicotine injections, which led to an improvement in working and episodic memory compared to non-treated transgenic mice

Evidence 3f3ab35e6e

Like the young mice, they also displayed an improvement in spatial memory, demonstrating that nicotine enhances memory in both young and old mice

Evidence 4a8fb3d7fa

The amount of Abeta was quantified, and following nicotine injections a reduction in Abeta, particularly in the oligomeric form, was found

Evidence f711621ab4

The long-term nicotine treatment caused faster tau aggregation in CA1 pyramidal neurons

Evidence c0daf1f8b6

The possible mechanism by which nicotine enhances the aggregation of tau is through the activation of p38-MAP kinase

Evidence d954e63dac

Even though nicotine showed a positive effect reducing plaque load (Hellstrom-Lindahl et al., 2004; Inestrosa et al., 2013; Nordberg et al., 2002), its use in AD treatment should be limited due to its toxic effect on tau pathology

Evidence 89d3bb280d

Wild-type mice treated with nicotine or with SSR180711, another partial agonist of alpha7 (Biton et al., 2006), showed increased LTP, while the transgenic AD model APPSwe/PS1DE9 showed no effect on LTP following SSR180711 treatment

Evidence a8b6451438

Simvastatin (SV) is a statin commonly used in the clinic to control cholesterol levels and it was shown to improve cognitive function in AD patients (Simons et al., 2002; Sparks et al., 2006)

Evidence d0605a9587

In a study conducted by Zhi et al. (2014), this molecule was used to treat a mouse model obtained with injections of the peptide Aß25-35. Administration for 11 days of SV improved memory performance in the Morris water maze task and promoted survival of CA1 pyramidal cells. This effect was proposed to be promoted by alpha7 nAChRs, since it is blocked by MLA administration (Zhi et al., 2014)

Evidence 5815561903

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)

Evidence 1a8e636017

Whilst the spatial memory deficit was restored by 4OH-GTS-21 treatment, this molecule had no effect on neuronal density (Ren et al., 2007)

Evidence 0571c6b56f

A novel molecule called PTI-125 was used to interfere with the interaction of FLNA and alpha7. The treatment with PTI-125 prevents FLNA binding to alpha7 and as consequence reduces the affinity of Abeta for nAChRs, attenuating the toxic effect of Abeta (Wang et al., 2012)

Evidence f88aa178c5

Another molecule investigated was 2-[2-(4- bromophenyl)-2-oxoethyl]-1-methyl pyridinium (S 24795), a partial alpha7 nAChR agonist. When this molecule was applied to synaptosomal preparations from rat frontal cortex and post mortem human AD samples it was able to dissociate Abeta in a concentration dependent manner

Evidence e73e1387f6

The incubation with S 24795 was able to normalize Ca++ influx mediated by both alpha7 nAChR and NMDAR (Wang et al., 2009, 2010)

Evidence 3fabe72c06

The subtype alpha4beta2 is characterized by lower calcium ion permeability and a slow desensitization rate compared to the homopentameric alpha7 nAChR (Quick and Lester, 2002)

Evidence f36e02dbff

The contextual fear conditioning and the novel object recognition tasks both showed that the cognitive deficits worsen when alpha7 is absent

Evidence 345f759d11

Arora et al. (2013) investigated, in a cellular system, the effect of prolonged Abeta exposure on nAChR function. The rodent neuroblastoma cell line NG108-15 was transfected with alpha4beta2 nAChRs and treated for three days with 100 nM Abeta. The following acute stimulation with Abeta and nicotine led to receptor activation that caused a perturbation of intracellular calcium homeostasis followed by mitochondrial dysfunction and increased oxidative stress (Arora et al., 2013)

Evidence a756992301

The oligomeric form of Abeta1-40 was able to activate alpha7 nAChR expressed in SH-SY5Y cell line (Lilja et al., 2011)

Evidence 1063627fea

In addition, anatomical studies in AD patients showed a massive loss of brain white matter and a specific reduction of cholinergic neurons of the basal forebrain (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Kim et al., 2013; Whitehouse et al., 1981, 1982)

Evidence 558891d58e

Several studies demonstrated the pivotal role of these cholinergic nuclei in cognitive functions

Evidence 90ef380467

The role of the cholinergic system in cognition and the modification observed in neurodegenerative diseases, and in particular in the case of AD, led to the formulation of the “cholinergic hypothesis” of geriatric disorders (Bartus et al., 1982; Contestabile, 2011), according to which the reduction in cholinergic innervation is responsible for the cognitive decline observed in AD patients

Evidence 4cfdbf7792

The cholinergic system is also involved in attention processes (Muir et al., 1993; Sarter and Bruno, 1997; Wenk, 1997)

Evidence 0bf0baa9c1

In a mouse model, the lack of ACh receptors in the prefrontal cortex (PFC) was demonstrated to be responsible for attention deficit, restored by the expression of the receptor in this area (Guillem et al., 2011)

Evidence 905076fa5b

The alpha7 homomeric receptor demonstrates a wide-spread localization in the brain and is characterized by a high calcium ion permeability and a fast desensitization rate (Dani and Bertrand, 2007; Quick and Lester, 2002)

Evidence 64bbd5e938

alpha7 nAChR on presynaptic terminals mediate release of others neurotransmitters (Wonnacott et al., 2006), while a postsynaptic or somatic localization elicits important changes in intracellular Ca++ concentration, that can activate second messenger pathways mediating cellular processes such as neuronal survival and gene expression (Berg and Conroy, 2002; Messi et al., 1997; Morley and Happe, 2000)

Evidence 5d402c7782

Moreover, it was demonstrated that the activation of alpha7 nAChRs is important during development for the maturation of glutamatergic synapses (Lozada et al., 2012)

Evidence f38073db1d

In a different study, rat hippocampus and cortex were investigated and the activation of both alpha7 and non-alpha7 receptors was obtained with an enhancement of Ca++ influx into the neuron following the application of picomolar (pM) concentrations of Abeta1-42

Evidence be8c4419e7

This enhancement of synaptic plasticity and the activation of intracellular pathways are mediated by the activation of alpha7 nAChRs (Dineley et al., 2001; Parri et al., 2011; Plant et al., 2003; Puzzo et al., 2008)

Evidence fb0f6d4367

It was proposed that the positive action of PREGS is mediated by alpha7 nAChR

Evidence 7f0b1f7caf

Subsequently, competition studies performed by incubating alpha7 nAChRs with Abeta and alpha-Bungarotoxin showed that the application of alpha-Bungarotoxin is able to decrease the amount of Abeta bound to alpha7 nAChRs, suggesting that both molecules compete for the same ligand binding domain (Wang et al., 2000b)

Evidence 9c91f0abc2

In both hippocampal interneurons and oocytes they observed a block of beta2*-nAChRs, that could be prevented by the application of a positive allosteric modulator (PAM) specific for beta2 subunit containing receptors, desformylflustrabromine (dFBr) (Pandya and Yakel, 2011)

Evidence 11e2e429a8

This AD model displays spatial memory deficit at 13-16 months of age, while APP-alpha7KO mice did not exhibit any memory deficit, suggesting that the absence of the alpha7 subunit of the nicotinic receptor protects against the behavioural deficit caused by expression of the mutated forms of APP in this AD model

Evidence 569422422d

In the APP-alpha7KO line the lack of alpha7 was sufficient to preserve synaptic terminals and dendrites, rescuing levels of synaptophysin and MAP2 to reach that of aged-matched WT controls

Evidence 62e203b384

Signs of neuropathology were found in APP-alpha7KO illustrated by loss of MAP2 immunoreactivity in the hippocampus

Evidence 3f3bed98d1

The authors postulated that the absence of alpha7 could prevent Abeta intracellular accumulation ameliorating the cognitive neuropathology and its phenotypic association (Dziewczapolski et al., 2009)

Evidence 191deeacfd

In the hippocampus, it was shown that APP-alpha7KO mice had high levels of Abeta, although significantly less than APP mice, an effect which is not due to modification of the APP expression level,equivalent in the two lines

Evidence 48617d3972

They showed that alpha7 subunits co-localize with Abeta1-42 in senile plaques of brain slices obtained from patients that suffered from sporadic AD

Evidence f0cd28fca5

The mechanism proposed is that the Aß-alpha7 nAChR interaction could activate neuroprotective downstream pathways (Parri et al., 2011), and that at the same time the interaction engages Abeta preventing its aggregation

Evidence 3f1037d441

However, it is clear that nAChR-Aß interaction initiates intracellular signalling implicating a set of transduction cascades

Evidence f67c446778

On the other hand, an opposite effect was shown with Abeta-nAChR interaction being responsible for inhibition of survival pathways

Evidence 36e9cabdbd

The neurotransmitter ACh binds to two families of receptors, nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs). Both families of receptors regulate the cognitive processes mentioned above (Ghoneim and Mewaldt, 1977; Petersen, 1977; Sarter and Paolone, 2011), and are both affected in AD

Evidence bb32b204d1

The five subunits that compose the receptor are assembled around a central hydrophilic pore that mediates the flow of the cations K+, Na+ and Ca++. In the human nervous system, there are eight alpha subunits (alpha2-alpha7, alpha9, alpha10) and three beta subunits (beta2-beta4) that assemble in different combinations to generate a variety of nAChR subtypes with distinct electrophysiological properties and brain localization (Albuquerque et al., 2009; Gotti et al., 2006b, 2007, 2009)

Evidence 28ca593e4e

These experiments confirmed that the level of expression of APP and the consequent synthesis of Ab were comparable between mouse lines, demonstrating that the difference in cognitive deficit and neuropathology were mediated exclusively by the nicotinic recept

Evidence 76e1e5adf8

This kinase is sensitive to Ca++, whose levels are increased following nAChR activation (Oddo et al., 2005)

Evidence 1a43945273

The intracellular signalling initiated by the binding of Abeta to nAChR at the cell surface requires the recruitment of Filamin A (FLNA), a scaffold protein that is known to crosslink actin, and in addition could also have a function in certain intracellular pathways (Stossel et al., 2001)

Evidence d325f57f75

Experiments performed with fragments of Abeta helped identify the sequence responsible for the interaction with alpha7, which corresponds to the amino acid residues 12-28 of the Abeta sequence (Wang et al., 2000b)

Evidence d00008abe4

This subunit commonly forms heteropentameric receptors in combination with the alpha4 subunit

Evidence 3c6471b8c3

In addition to the alpha4beta2 subtype, it was demonstrated that the alpha7 subunit is able to coassemble with the beta2 subunit to form a heteropentameric receptor

Evidence 973cc0af5f

Under these experimental conditions, alpha7 and beta2 are able to co-assemble into a functional receptor that localizes at the cell surface

Evidence 3828c03dde

Wang et al. showed that the association between FLNA and the alpha7 subunit is elevated in AD samples compared to age matched controls

Evidence a1e2c58fcb

In addition, several authors observed a reduction in the activity of acetylcholinesterase (AChE), the enzyme that metabolises ACh after its release in the synaptic cleft (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Davies and Maloney, 1976; Perry et al., 1978)

Evidence 4512632581

In addition to nAChRs and mAChRs, the enzyme choline acetyltransferase (ChAT), involved in ACh production, is also affected in AD. The activity of this ChAT enzyme, and consequently the synthesis of ACh, is decreased in AD brains

Evidence 37947d859a

The importance of beta2 in maintaining brain homeostasis during normal ageing was highlighted in the KO mouse for this subunit

Evidence 8adf0ee1b3

Null mutant beta2 mice were also tested to determine the role of this subunit in cognition. Guillem et al. (2011) showed that these mice exhibit an attention deficit which was restored by re-expression of this subunit with a lentiviral vector in the PFC

Evidence e6299d662c

Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986)


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