beta-Amyloid (Abeta) is also an important factor, which may initiate and promote AD (Selkoe 1999)
Administration of the nicotinic antagonist mecamylamine to elderly subjects and AD patients has produced cognitive impairment (Newhouse and Kelton 2000)
Nerve growth factor intraventricularly administered to AD patients for 3 months resulted in an increased [11C]nicotine binding (Eriksdotter-Jo¨nhagen et al 1998), whereas treatment with the 5-HT3 blocker ondansetron showed a decreased number of cortical nAChRs (Nordberg et al 1997)
Cholinergic therapy is based on the assumption that low levels of acetylcholine are responsible for the cognitive decline associated with AD
It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000)
Estrogen, which in epidemiologic studies has been shown to reduce the risk of AD (Henderson 1997), has in experimental studies in PC 12 cells shown neuroprotective effects against Abeta toxicity that are at least partly mediated by the alpha7 subtype nAChR (Svensson and Nordberg 1998)
Activation of the nAChR modulates the release of several neurotransmitters (Kaiser et al 2000; Wonnacott 1997) that mediate important physiologic mechanisms including cognitive functions
The potential therapeutic benefit of nAChR stimulation in AD is based upon the fact that nicotine improves memory in animals, healthy subjects, and AD patients (Levin 2000; Newhouse and Kelton 2000; Newhouse et al 1997; Rusted and Warburton 1992)
Acute administration of nicotine to AD patients has resulted in a measurable short-term improvement in learning, memory, and attentional performance (Jones et al 1992)
Since an enhanced activity of acetylcholinesterase has been measured in cerebrospinal fluid following long-term treatment with tacrine (Nordberg et al 1999), possibly as a result of an increased acetylcholinesterase gene expression, it might be an advantage to use drugs interacting with nAChRs
In addition, PET studies also have revealed an improvement in nAChRs in AD patients during long-term treatment with cholinesterase inhibitors such as tacrine and NXX- 066 (Nordberg 2000; Nordberg et al 1992, 1998)
Positron emission tomography studies have revealed a reduced cortical acetylcholinesteserase activity in AD patients (Iyo et al 1997; Kuhl et al 1999)
The levels of alpha4 and alpha7 nAChR mRNA showed a decrease with aging, whereas the levels of alpha3 mRNA were unchanged in the elderly brain relative to the fetal brain (Hellstro¨m-Lindahl et al 1998)
A decrease in protein levels of the alpha4 nAChR but not of the alpha3 and alpha7 nAChRs was reported by Martin-Ruiz et al (1999)
Lee et al (2000) recently also reported a significant decrease in the alpha7 nAChR protein level of the AD hippocampus
Interestingly, a reduction in the protein level of alpha7 has also been measured in the frontal cortex of patients with schizophrenia (Guan et al 1999), whereas no decrease was measured in the alpha4 nAChR protein level (Guan et al 1999)
Possible factors such as amyloid peptide accumulation, hyperphosphorylation of tau protein, oxidative stress, and modification of cell membrane during the development of AD may be related to decreased protein levels of nAChRs (Farooqui et al 1995; Smith et al 1996)
Experimental data suggest that the nAChRs might act as neuromodulators in communicative processes in the brain (Kaiser et al 2000; Lindstro¨m 1997; Wonnacott 1997)
Recently, the nicotinic agonist ABT- 418 improved verbal learning and memory on a selective reminding task in AD patients (Potter et al 1999)
The presynaptic vesicular acetylcholine transporter vesamicol ([123I]iodobenzovesamicol) has been used in vivo as a marker of presynaptic cholinergic activity in single photon emission computed tomography (SPECT) studies (Kuhl et al 1996)
A significant decrease in [3H]epibatidine binding has been observed with aging in the human cortical brain regions and cerebellum (Marutle et al 1998)
In addition, a marked reduction in the laminar distribution of [3H]epibatidine binding was observed in control cortical tissue with aging (Figure 1)
Interestingly enough, a considerable body of evidence exists to suggest that the nAChRs are involved in cognitive and memory functions (Levin 2000; Newhouse and Kelton 2000; Newhouse et al 1997; Sahakian and Coull 1994)
A progressive loss of cortical acetylcholinesterase activity has been observed in AD patients with cognitive decline (Shinotoh et al 2000)
A significant correlation can be observed between cognitive function and nicotinic receptor binding (k2*) (Figure 3A)
Interestingly enough, lipid peroxidation has been shown to decrease the number of nAChRs in PC12 cells (Guan et al 2000a)
The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)
A consistent, significant loss of nAChRs has been observed in cortical autopsy brain tissue from AD patients relative to age-matched healthy subjects (Nordberg and Winblad 1986)
The cortical nAChR deficits significantly correlate with cognitive impairment in AD patients (Nordberg, in press; Nordberg et al 1995, 1997)
Significant reductions in the number of nAChRs were measured in cortical regions of Swedish APP 670/ 671 mutation (273% to 287%) (Marutle et al 1999)
When the laminar binding distribution of [3H]nicotine, [3H]epibatidine, and [3H]cytisine was measured in AD cortical autopsy tissue, marked reductions were observed relative to control brains (Sihver et al 1999c) (Figure 1)
A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b)
This mutation at codon 670/671 on the APP gene on chromosome 21 was discovered in a Swedish family, and the mutation is unique in the sense that it is the only AD mutation that has been shown to alter the APP metabolism, resulting in an overexpression of the amyloid leading to plaque formation (Mullan et al 1992)
Examination of the regional expression of mRNA of the nAChR alpha4 and alpha3 subunits has shown no difference in autopsy AD brain tissue in any region analyzed (Hellstro ¨m-Lindahl et al 1999; Terzano et al 1998), whereas the level of the alpha7 mRNA was significantly higher in the hippocampus (Hellstro¨m-Lindahl et al 1999)
The loss in cortical acetylcholinesterase activity was less pronounced in mildly demented AD patients relative to autopsy material and did not strictly correlate with cerebral glucose metabolism impairment (Kuhl et al 1999)
Selective cortical deficits in [11C]nicotine binding are often observed by PET early in the course of the AD disease (Figure 3A)
A ligand with a selectivity for the alpha4beta2 nAChRs would be particularly preferable because the alpha4beta2 has been recognized as the predominant subtype that is deficient in AD (for a review, see Sihver et al 2000)
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.