Nicotinic Receptors, Amyloid-β, and Synaptic Failure in Alzheimer’s Disease

Jürgensen, Sofia; Ferreira, Sérgio T.

doi:10.1007/s12031-009-9237-0

Cited by 51 publications

(51 citation statements)

References 91 publications

(112 reference statements)

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“…In AD, synaptic dysfunction and failure are closely related to the clinical symptoms [22]. In this study, we investigated a role for neuritin in the cellular and cognitive features of AD.…”

Section: Discussionmentioning

confidence: 99%

Neuritin Attenuates Cognitive Function Impairments in Tg2576 Mouse Model of Alzheimer's Disease

et al. 2014

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Neuritin, also known as CPG15, is a neurotrophic factor that was initially discovered in a screen to identify genes involved in activity-dependent synaptic plasticity. Neuritin plays multiple roles in the process of neural development and synaptic plasticity, although its binding receptor(s) and downstream signaling effectors remain unclear. In this study, we found that the cortical and hippocampal expression of neuritin is reduced in the brains of Alzheimer's disease (AD) patients and demonstrated that viral-mediated expression of neuritin in the dentate gyrus of 13-month-old Tg2576 mice, an AD animal model, attenuated a deficit in learning and memory as assessed by a Morris water maze test. We also found that neuritin restored the reduction in dendritic spine density and the maturity of individual spines in primary hippocampal neuron cultures prepared from Tg2576 mice. It was also shown that viral-mediated expression of neuritin in the dentate gyrus of 7-week-old Sprague-Dawley rats increased neurogenesis in the hippocampus. Taken together, our results demonstrate that neuritin restores the reduction in dendritic spine density and the maturity of individual spines in primary hippocampal neurons from Tg2576 neurons, and also attenuates cognitive function deficits in Tg2576 mouse model of AD, suggesting that neuritin possesses a therapeutic potential for AD.

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“…In AD, synaptic dysfunction and failure are closely related to the clinical symptoms [22]. In this study, we investigated a role for neuritin in the cellular and cognitive features of AD.…”

Section: Discussionmentioning

confidence: 99%

Neuritin Attenuates Cognitive Function Impairments in Tg2576 Mouse Model of Alzheimer's Disease

et al. 2014

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Section: Nicotinic Acetylcholine Receptors (Nachrs) As a Therapeutic mentioning

confidence: 99%

“…These receptors are localized throughout the cortex, hippocampus, amygdala, hypothalamus, striatum, and other regions involved in these cognitive processes [13]. Because decreased levels of these receptors have been found in AD brains [58], this reduction is considered to explain, at least in part, the cognitive deficits in AD.The α7 receptors are very important for mediating sensory gating, attention and learning, and memory, making them an ideal target to improve these cognitive functions. However, these receptors are susceptible to agonist-induced desensitization, a characteristic that complicates the use of agonists as therapeutic agents.…”

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confidence: 99%

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Echeverrı́a

Zeitlin

2012

CNS Neuroscience & Therapeutics

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SUMMARYTobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD. Alzheimer's disease: The Cholinergic System as a Therapeutic TargetAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia [1,2]. The disease is characterized by extracellular accumulation of senile plaques, mainly composed of aggregated forms of the amyloid-beta peptide (Aβ), as well as intracellular accumulation of neurofibrillary tangles of the microtubule-associated protein tau [1]. These neuropathological changes are associated with structural brain abnormalities, inflammation, and cognitive impairment such as impairment of working memory in AD patients. The progressive loss of memory in AD patients correlates with increased levels of Aβ and the deterioration of the cholinergic system in the brain. The degenerative process involves a sequence of pathological events, including early degeneration of the cerebral basal forebrain and subsequent deterioration of the cortical cholinergic system [3,4]. This deterioration commonly includes a reduction in the levels of acetylcholine (ACh) and α3, α4, and α7 nicotinic ACh receptors (nAChRs) as well as a decrease in the activity of choline acetyltranferase in the brain [5].Of these nAChRs, the α7 receptors are considered to be ideal therapeutic targets for several neurological conditions, including AD, schizophrenia, and Parkinson's disease (PD) as well as tobacco addiction [6,7]. The α7nAChR is a homomeric pentamer that has a high permeability to calcium (P Ca :P Na ≈ 10), and undergoes rapid and reversible desensitization and pronounced inward rectification [8]. The α7 subunit is highly expressed in the cortex, hippocampus, and hypothalamus [8], and has also been suggested to have functionally important expression in ...

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“…The predominant clinical symptoms early associated with Alzheimer’s disease (AD) include a deficiency in memory capabilities and these deficits are linked to a selective impairment of cholinergic function (Buckingham et al, 2009; Jürgensen and Ferreira, 2010). It has been reported that a significant decrease in the number of α4 nicotinic acetylcholine receptors (nAChRs) is one of the earliest events in the pathogenesis of AD (Burghaus et al, 2000) even preceding cholinergic neuronal degeneration.…”

Section: Introductionmentioning

confidence: 99%

“…Aβ can interact in different ways with the nAChRs depending on the receptor subtype as well as on Aβ peptide concentration or type of preparation (monomers versus oligomers) or incubation times (Jürgensen and Ferreira, 2010). It seems that Aβ might bind with high affinity (picomolar range) to α7 receptors (Wang et al, 2000; Khan et al, 2010; Tong et al, 2011), although this remains controversial (Small et al, 2007), and produces both stimulatory (Dougherty et al, 2003; Puzzo et al, 2008; Mura et al, 2012) and inhibitory effects (Liu et al, 2001; Pettit et al, 2001) suggesting a distinct regulatory role depending on the receptor location (Tong et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Effects of soluble Î²-amyloid on the release of neurotransmitters from rat brain synaptosomes

Olivero

Grilli

Chen

et al. 2014

Front. Aging Neurosci.

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Contradictory results have been reported on the interaction of beta-amyloid (Aβ) with cholinergic receptors. The present paper investigates the modulatory effect of Aβ1-40 on the neurotransmitter release evoked by nicotinic (nAChRs) and muscarinic (mAChRs) receptors. Aβ1-40 inhibits both nicotinic and muscarinic-evoked [3H]DA overflow from rat nerve endings. Added to perfusion medium, Aβ1-40 is able to enter into synaptosomes; it exerts its inhibitory effect at extracellular sites when release is stimulated by nAChRs and intracellularly when release is evoked by mAChRs. Moreover, our data show that Aβ1-40 acts as non competitive antagonist of heteromeric α4β2* but not of α3β4* nAChRs which modulate [3H]NA overflow. Positive allosteric modulators of nAChRs counteract its inhibitory effect. It might be that compounds of this type could be useful to prevent, slow down the appearance or reverse the cognitive decline typical of the normal processes of brain aging.

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Nicotinic Receptors, Amyloid-β, and Synaptic Failure in Alzheimer’s Disease

Cited by 51 publications

References 91 publications

Neuritin Attenuates Cognitive Function Impairments in Tg2576 Mouse Model of Alzheimer's Disease

Neuritin Attenuates Cognitive Function Impairments in Tg2576 Mouse Model of Alzheimer's Disease

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Effects of soluble Î²-amyloid on the release of neurotransmitters from rat brain synaptosomes

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