Paper Summaries

Paper #1

This study aimed to investigate whether nicotinic stimulation will can enhance cognitive function in patients with AD.  It has been shown that the nicotinic receptor system is important in attention, spacial memory, and verbal learning. The study used six non-smoking adults with AD and gave them specific cognitive battery tests, selective reminding tasks, recognition memory tasks, RAT test, and spacial memory tasks. The ABT-418 drug was given to the patients as well. After careful analysis, the ABT-418 drug was found to lead to an increase in total words recalled and a decline in recall failures. In addition, improvements in spatial memory, recognition tasks, and RAT tasks had similar dose-related effects. 

Citation: Potter, A., Corwin, J., Lang, J. et al. Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer’s disease. Psychopharmacology 142, 334–342 (1999). 

Paper #2

This study aims to understand the effects of the nicotinic antagonist Mecamylamine on cognitive functioning in people with AD. The use of the antagonist in the study allows for the researchers to identify the specific cognitive operations affected by the interruption of agonists. The study utilized 12 healthy young males and 15 elderly subjects. They were administered various learning and memory tests, while administering increasing doses of Mecamylamine. It was found that the 20mg dose caused an increase in errors on the RAT tasks. The 10mg dose revealed significant significant memory impairment in the elderly subjects and not the healthy adults. In addition, a decrease in reaction time related to dose-response was also observed. This shows that blocking nicotinic receptor functions cause considerable cognitive impairment. 

Citation: Newhouse, P., Potter, A., Corwin, J. et al. Age-Related Effects of the Nicotinic Antagonist Mecamylamine on Cognition and Behavior. Neuropsychopharmacol 10, 93–107 (1994). 

Paper #3

In humans, blocking certain muscarinic receptors can have negative cognitive effects similar to what is experienced by patients with AD. Specific blood flow abnormalities in the brain have also been linked with AD.  In this study, the researchers administered nicotinic and muscarinic receptor blockade to seven healthy elderly participants, and they performed rCBF testing. The researchers found a reduction in frontal cortex blood flow. The differences in blood flow may be attributed to loss of nicotinic receptors.

Citation: Gitelman, Darren R., and Isak Prohovnik. "Muscarinic and nicotinic contributions to cognitive function and cortical blood flow." Neurobiology of aging 13.2 (1992): 313-318.

Paper #4

This study aims to determine whether impairment of the cholinergic system is present in the early stages of AD. To do this acetylcholine esterase activity was measured within the amygdala and cerebral neocortex using PET scans. The study measured nine patients with AD, and were compared with thirteen healthy control group members.  The researchers found that AChE activity in the amygdala and cerebral cortex was diminished. The results from the study further add to the idea that changes in the cholinergic systems are present in the beginning of and can lead to the development of AD.

Citation: Herholz, Karl, et al. "In vivo study of acetylcholine esterase in basal forebrain, amygdala, and cortex in mild to moderate Alzheimer disease." Neuroimage 21.1 (2004): 136-143.

Paper #5

Loss of ChAT activity in the brain is associated with dementia severity, yet whether ChAT activity is correlated with early cognitive impairment is unknown. The study utilized brain tissue samples from 58 individuals either diagnosed without cognitive impairment, with  mild cognitive impairment, or having mild AD. ChAT activity was measured in the hippocampus and four separate cortical regions. The study revealed that ChAT levels in the hippocampus of participants with MCI were elevated above those with no cognitive impairment, yet ChAT activity remains the same in individuls with mild AD. They also found evidence that cholinergic upregulation can happen in more than one area of the brain in people with MCI. They concluded that other changes in the brain besides cholinergic loss are responsible for early cognitive impairment in individuals with AD.

Citation: DeKosky, Steven T., et al. "Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment." Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 51.2 (2002): 145-155.

Paper #6

In this study, the researches wanted to observe the deficit in cholinergic systems in the brain, reduced ChAT affinity, and reduced choline affinity in individuals with AD. The study consisted of 4 clinically evaluated individuals with AD, and 11 control group members without any cognitive impairment. The study found that the levels of ChAT activity were reduced to the same extent as nicotinic binding sites in the frontal cortex of AD patients. They also measured a decrease in release of ACh in the postmortem brain tissues.

Citation: Nordberg, Agneta, and Bengt Winblad. "Reduced number of [3H] nicotine and [3H] acetylcholine binding sites in the frontal cortex of Alzheimer brains." Neuroscience letters 72.1 (1986): 115-120.

Paper #7

It is known that nicotine improves the memory and learning of experimetal animals. In this study, the researchers wanted to investigate the effects of Lobeline, a nicotinic receptor agonist, on memory. The study utilized male rats and gave them lesions of the septal area. After surgery, the rats were trained on completing the Morris water maze. During the first four days of training, Lobeline was administered fifteen minutes before. They found that administering the Lobeline to the rats with septal lesions greatly improved their performance in water maze. Their findings could suggest that Lobeline offers the similar effects to nicotine with respect to memory and memory performance. 

Citation: Decker, Michael W., Mark J. Majchrzak, and Stephen P. Arnerić. "Effects of lobeline, a nicotinic receptor agonist, on learning and memory." Pharmacology Biochemistry and Behavior 45.3 (1993): 571-576.

Paper #8

Functional abnormalities in muscarinic and nicotinic receptors are associated with complications in individuals with AD. This study attempts to examine selective muscarinic and nicotinic receptopr antagonism and its effects on various cognitive processes. The study utilized 12 healthy volunteers, and was a double-blind experiment that used a placebo along with doses of mecamylamine and scopolamine drugs. The volunteers completed the CDR assessment online, along with various assessments that test declarative memory, spacial memory, and psychomotor function. The study found that blocking the muscarinic receptors was correlated with impairments in working memory, spacial memory, and psychomotor function. They also found that blocking the nicotinic receptors with mecamylamine had little effect on cognitive processing. In addition, they found that blocking both muscarinic and nicotinic receptors impaired all cognitive processes. These results suggest that muscarinic and nicotinic receptors interact in some way.

Citation: Ellis, Julia R., et al. "Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans." International Journal of Neuropsychopharmacology9.2 (2006): 175-189.

Paper #9

The drug scopolamine, which is capable of creating impairment in memory processes, was investigated in this study. The researchers wanted to examine the effects of doses of scopolamine on cognitive functions that are impaired in individuals with AD. Twenty healthy volunteers were evaluated using various cognitive tests, while being given various doses of scopolamine, methylscopolamine, or a placebo. Reaction time, choice reaction time, visual selective attention, sustained attention, verbal learning, and covert orientation were all tested. The study revealed that most of the tests were affected by a linear dose-dependent way, and that verbal learning was greatly impaired at the highest doses of scopolamine. No impairment was created with verbal short-term memory or spatial learning. 

Citation: Broks, P., et al. "Modelling dementia: effects of scopolamine on memory and attention." Neuropsychologia 26.5 (1988): 685-700.

Paper #10

This study wanted to examine the brain's response to cholinesterase inhibitor physostigmine in patients with AD compared to healthy patients. The study utilized seven brains to base their observations on. The study found that the distributions of AChE in the brain are greatly altered in patients with AD, and that cholinesterase inhibitors have an effect on enzymatic function of plaques and tangles. Physostigmine was found to greatly inhibit plaque and tangle cholinesterases. 

Citation: Mesulam, M‐Marsel, Changiz Geula, and M. Asuncion Morán. "Anatomy of cholinesterase inhibition in Alzheimer's disease: effect of physostigmine and tetrahydroaminoacridine on plaques and tangles." Annals of neurology 22.6 (1987): 683-691.

Paper #11

A common symptom of AD is the build up od B-amyloid plaques in the brain. In this study, the researchers treated mice that were carrying an amyloid precursor protein. These mice were treated with nicotine drinking fluid to see if a reduction in in these plaques will occur. They began the study with nine month old mice, and had an estimated daily intake of 25-35mg of nicotine. The study also utilized a control group of mice that received a sucrose solution. The mice were then killed by cervical dislocation in order to perform an analysis of their brain. They found that both male and female rats that received the nicotine solution saw a reduction in plaques and plaque density in the frontoparietal, hippocampus, and olfactory tract. Males also had a more dramatic reduction in plaque in the frontal cortex. 

Citation: Nordberg, Agneta, et al. "Chronic nicotine treatment reduces β‐amyloidosis in the brain of a mouse model of Alzheimer's disease (APPsw)." Journal of neurochemistry 81.3 (2002): 655-658.

Paper #12 

It is known that nAChR binding decreases with age, yet it has not yet been determined what specific subunits deteriorate to contribute to symptoms of AD. This study is the first to utilize immunoprecipitation techniques to study the subunit composition of nAChRs, and investigates the loss of nAChR subunits that contribute to difficulty binding in the temporal cortex and striatum. Tissue was obtained with patients' consent, and past criteria indicated the presence of dementia or PD. The study found that alpha4 and beta2 containing receptors are the most dominant nAChRs in the neocortex and striatum. They concluded that therapies targeting nAChRs can best treat patients with AD, PD, and DLB. 

Citation: Gotti, Cecilia, et al. "Selective nicotinic acetylcholine receptor subunit deficits identified in Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies by immunoprecipitation." Neurobiology of disease 23.2 (2006): 481-489.

Paper #13

This current study aims to understand the relationship between alphaBGT and nicotine binding in the thalamus in patients with schizophrenia and DLB. 12 samples of brain tissue were obtained from patients that meet the diagnostic criteria, and 12 control cases that were free of schizophrenia and DLB. Nicotine receptor autoradiography was then analyzed and an average value for the intensity of binding in the nucleus was measured. They found that in both patients with schizophrenia and DLB, average values of alphaBGT were greatly reduced in the reticular nucleus. They also found a slight loss of binding in the lateral dorsal nucleus. 

Court, Jennifer, et al. "Neuronal Nicotinic Receptors in Dementia with Lewy Bodies and Schizophrenia: α‐Bungarotoxin and Nicotine Binding in the Thalamus." Journal of neurochemistry 73.4 (1999): 1590-1597.

Paper #14

It is known that the build up of amyloid-beta peptide and the loss of interaction between cholinergic mechanisms contribute to the development of AD. In this study, the researchers wanted to understand whether the deletion of alpha-7 nicotinic receptors inhibits the amyloid-beta peptide function, thus creating an increase in the peptide that triggers a pathology similar to AD. The study was performed on mice who were subjected to fear-conditioning tests and a novel object recognition test. The study found that the deletion of these receptors caused impairment of synaptic plasticity in the hippocampus at 12 months. This is complemented by an increase in amyloid-beta peptide and Amyloid Precursor Protein.

Citation: Tropea, Maria Rosaria, et al. "Genetic deletion of α7 nicotinic acetylcholine receptors induces an age-dependent Alzheimer’s disease-like pathology." Progress in Neurobiology206 (2021): 102154.

Paper #15

This study aims to investigate the effects of low doses of methyllycaconitine, a selective antagonist, on alpha-7 nicotinic acetylcholine receptors. The study was performed on male rats. The researchers concluded that MLA potentiated receptor activity, leading to an increase on calcium. In addition, low doses of MLA improve memory acquisition processes, but not memory consolidation. MLA increased hippocampal glutamate efflux. This showed that a selective nicotinic receptor can help to improve memory in people with AD, and offer an alternative treatment option. 

Citation: van Goethem, Nick P., et al. "Antagonizing α7 nicotinic receptors with methyllycaconitine (MLA) potentiates receptor activity and memory acquisition." Cellular Signalling 62 (2019): 109338.

Paper #16

There is very little evidence that indicates the behavioral effects that alpha-7 receptors have. This study attempts to use alpha-7 null mutant mice with the drug amphetamine to demonstrate the role of dopamine in a discriminative response to nicotine. The study used 21 male mutant mice against a control group of 22 wild-type mice. The mice were then subjected to drug discrimination training procedures. The study found that the deletion of the gene that codes for the alpha-7 subunit on nicotinic receptors can affect the nicotinic discriminative stimulus characteristics.  In addition, MLA was observed to weaken responses to nicotine and amphetamine in the wild-type control mice. At certain doses, the abililty of mutant mice to discriminate between nicotine and amphetamine was weakened as well.

Citation: Quarta, D., Naylor, C.G., Barik, J. et al. Drug discrimination and neurochemical studies in α7 null mutant mice: tests for the role of nicotinic α7 receptors in dopamine release. Psychopharmacology 203, 399–410 (2009).

Paper #17

It is known that AChE localizes with amyloid-beta peptide deposits in the brains of people with AD.  The study found AChE to be a strong amyloid-beta protein promoting factor. The researchers then hypothesized that AChE may be able to accelerate amyloid-beta formation and can have a significant role in amyloid deposition in the brains of patients with Alzheimer's. 

Citation: Inestrosa, Nibaldo C., et al. "Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme." Neuron16.4 (1996): 881-891.

Paper #18

It is known that an excess of AChE alters the neuromuscular junctions in tadpoles. However, the researchers in this study want to determine the potential for cognitive decline in learning and memory when a cholinergic imbalance is present in mammals. The study utilized transgenic mice that express human AChE. The study found that the transgenic mice had a rapid decline in spatial memory as they aged into adulthood, demonstrated by the use of a water maze test. In terms of behavior, they found that the transgenic mice had a decreased response to the induction of hypothermia. These results indicate that alterations of cholinergic balance in the brain can cause physiological changes and the deterioration of memory in some patients with AD. 

Citation: Beeri, Rachel, et al. "Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice." Current Biology 5.9 (1995): 1063-1073.

Paper #19

It is known that GTS-21, a selective agonist of alpha-7 nicotinic receptors, can provide protective effects in animal models with neurodegenerative diseases. This study hypothesized that pretreatment of GTS-21 in aged rats will weaken cognitive decline with isoflurane exposure. A group of 20 month old rats were utilized in this study. The study found that exposure to isoflurane created new learning and memory deficits in older rats, which the GTS-21 was able to help mitigate. 

Citation: Kong, Fei-Juan, et al. "Alpha 7 nicotinic acetylcholine receptor agonist GTS-21 mitigates isoflurane-induced cognitive impairment in aged rats." journal of surgical research 194.1 (2015): 255-261.

Paper #20

The aim of this study was to investigate the effects of PNU-282987 on spatial learning and memory in both normal and chronically stressed transgenic mice. The study used wild-type mice and 39 transgenic mice. To evaluate spatial learning and memory, the rats were tested using the Morris water maze test at 3 months old. There were no significant results with respect to spatial memory in the experimental or control groups.  In addition, they're were no significant differences between each group in new cell proliferation.

Citation: Vicens, Paloma, et al. "Effects of an alpha7 nicotinic receptor agonist and stress on spatial memory in an animal model of Alzheimer's disease." BioMed research international 2013 (2013).

Paper #21

The aim of this study is to determine whether a correlation exists between the alpha-7 nicotinic acetylcholine receptor subunit and amyloid-beta peptide in the brains of patients with AD. Moreover, they want to investigate whether overexpression of the alpha-7 receptors could change the neurotoxicity of the amyloid-beta peptide. The expression of the receptors in patients with AD and healthy adults was determined using immunofluorescence. In addition, SH-SY5Y cells were utilized to silence or overexpress the alpha-7 receptor units. Post-mortem brain samples were obtained for use in the study. The study found that the expression of the amyloid-beta peptides in the brain increased significantly, while the expression of the alpha-7 receptor subunits had decreased compared to the samples taken from the healthy control group. The findings from the suggest that the alpha-7 receptors can protect the brainss of patients with AD against amyloid-beta peptides.

Citation: Ren, Jia-Mou, et al. "Expression levels of the α7 nicotinic acetylcholine receptor in the brains of patients with Alzheimer's disease and their effect on synaptic proteins in SH-SY5Y cells." Molecular Medicine Reports 22.3 (2020): 2063-2075.

Paper #22

The researchers in this study hypothesized that increased expression of the alpha-7 neuronal receptor can lead to cognitive enhancement at low doses. This was tested by examining the effects of AZD0238 using in vivo and ex vivo binding, along with cognitive function in rodents. The study used male mice, who were subjected to the novel object recognition test. The study found that a low dose of AZD0238 resulted in an upregulation of alpha-7 NNRs in the hippocampus and prefrontal cortex of the brain. In addition, an increase was observed in behavior of the mice during the novel object recognition test. AZD0238 unexpectedly produces a change in receptor number at low doses in rodent models. 

Citation: Werkheiser, J. L., et al. "Ultra-low exposure to alpha-7 nicotinic acetylcholine receptor partial agonists elicits an improvement in cognition that corresponds with an increase in alpha-7 receptor expression in rodents: implications for low dose clinical efficacy." Neuroscience 186 (2011): 76-87.

Paper #23

This study hypothesizes that spine changes in the alpha-7 nicotinic acetylcholine receptor knockout could explain deficits in behavior in alpha-7 knockout mice and changes in the hippocampus with the presence of AD. The researchers tested their hypothesis by the density of dendritic spines in the CA1 hippocampal neurons. The study utilized alpha-7 knockout mice, and performed golgi analysis on them. The researchers found that there were structural differences in the CA1 region of the hippocampus of the knockout mice, and were most obvious in the basal dendrites. The researchers concluded that the abscence of alpha-7 receptors can decrease maturation in the dendritic spine.

Citation: Morley, Barbara J., and R. F. Mervis. "Dendritic spine alterations in the hippocampus and parietal cortex of alpha7 nicotinic acetylcholine receptor knockout mice." Neuroscience233 (2013): 54-63.

Paper #24

The aim of this study is to determine whether changes in the GABAergic signals to the pyramidal neurons in the hippocampus are due to a decrease of cholinergic control from nicotinic receptors. Pyramidal cells in the hippocampus were recorded from groups of both young and old rats. The study determined that observations of GABAergic inhibition in older rats was more closely associated with the loss of various GABAergic interneurons within the brain.

Citation: Potier, B., et al. "Age-related alterations of GABAergic input to CA1 pyramidal neurons and its control by nicotinic acetylcholine receptors in rat hippocampus." Neuroscience142.1 (2006): 187-201.

Paper #25

The purpose of this study is to examine alpha-7 nicotinic acetylcholine receptors and amyloid-beta peptide in the superior frontal cortex across various stages of AD. The study utilized 29 elderly participants. The study found that, overall, as the development of AD continued, the total amyloid-beta concentrations increased within the superior frontal cortex, while the alpha-7 receptors remain the same within the frontal cortex. Moreover, increased receptor binding is associated with increased expression of amyloid-beta peptide.

Citation: Ikonomovic, Milos D., et al. "Cortical α7 nicotinic acetylcholine receptor and β-amyloid levels in early Alzheimer disease." Archives of neurology 66.5 (2009): 646-651.