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Anorexia is a behavioral change caused by functional brain disorders in patients with Alzheimer's disease (AD). Amyloid-β (1–42) oligomers (o-Aβ) are possible causative agents of AD that impair signaling via synaptic dysfunction. In this study, we used Aplysia kurodai to study functional disorders of the brain through o-Aβ. Administration of o-Aβ to the buccal ganglia (feeding brain for oral movements) by surgical treatment significantly reduced food intake for at least five days. Furthermore, we explored the effects of o-Aβ on the synaptic function in the feeding neural circuit, focusing on a specific inhibitory synaptic response in jaw-closing motor neurons produced by cholinergic buccal multi-action neurons because we recently found that this cholinergic response decreases with aging, which is consistent with the cholinergic hypothesis for aging. Administration of o-Aβ to the buccal ganglia significantly reduced the synaptic response within minutes, whereas administration of amyloid-β (1–42) monomers did not. These results suggest that o-Aβ may impair the cholinergic synapses, even in Aplysia , which is consistent with the cholinergic hypothesis for AD. • Amyloid-β oligomers (o-Aβ) were administrated to Aplysia buccal ganglia by surgery. • Administration reduced the food intake similar to anorexia in Alzheimer's disease. • Effect of o-Aβ on the feeding neural circuits within the ganglia was also explored. • Administration reduced a specific inhibitory cholinergic synaptic response. • The present results are consistent with the cholinergic hypothesis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is one of the leading causes of dementia today. This neurodegenerative disorder results in the progressive decline of cognitive ability and memory. The biochemical processes that characterize this disease include the formation of β-amyloid plaques, the development of neurofibrillary tangles, and the loss of cholinergic neurons in the cerebral cortex. In fact, most of the drugs available to deal with this disease are directed at the affectations suffered by diseased individuals in the cholinergic synapse of the Central Nervous System. It is for this reason that the development of drugs directed to therapeutic targets that allow increasing the availability of acetylcholine in the cholinergic synapse is a field of research of great interest. However, success in the clinical use of these compounds is limited by the side effects they produce and by the multifactorial nature of this disease. The present review aims to provide an overview of the cholinergic dysfunction observed in Alzheimer's disease patients that supports the cholinergic hypothesis in its pathophysiology. In addition, cholinesterase activity inhibitors of clinical and innovative use are discussed as an alternative symptomatic therapy for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced "chronic" multi-systems inflammatory disease(s) including Alzheimer's disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria's direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the "infection hypothesis" of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of "Pg bacteria" residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the "Gingipains Hypothesis", AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention. [ABSTRACT FROM AUTHOR]

Abstract: The perceptual differentiation of odors can be measured behaviorally using generalization gradients. The steepness of these gradients defines a form of olfactory acuity for odor quality that depends on neural circuitry within the olfactory bulb and is regulated by cholinergic activity therein as well as by associative learning. Using this system as a reduced model for age-related cognitive decline, we show that aged mice, while maintaining almost the same baseline behavioral performance as younger mice, are insensitive to the effects of acutely elevated acetylcholine, which sharpens generalization gradients in young adult mice. Moreover, older mice exhibit evidence of chronically elevated acetylcholine levels in the olfactory bulb, suggesting that their insensitivity to further elevated levels of acetylcholine may arise because the maximum capacity of the system to respond to acetylcholine has already been reached. We propose a model in which an underlying, age-related, progressive deficit is mitigated by a compensatory cholinergic feedback loop that acts to retard the behavioral effects of what would otherwise be a substantial age-related decline in olfactory plasticity. We also treated mice with 10-day regimens of olfactory environmental enrichment and/or repeated systemic injections of the acetylcholinesterase inhibitor physostigmine. Each treatment alone sharpened odor quality acuity, but administering both treatments together had no greater effect than either alone. Age was not a significant main effect in this study, suggesting that some capacity for acetylcholine-dependent plasticity is still present in aged mice despite their sharply reduced ability to respond to acute increases in acetylcholine levels. These results suggest a dynamical framework for understanding age-related decline in neural circuit processing in which the direct effects of aging can be mitigated, at least temporarily, by systemic compensatory responses. In particular, a decline in cholinergic efficacy can precede any breakdown in cholinergic production, which may help explain the limited effectiveness of cholinergic replacement therapies in combating cognitive decline. [Copyright &y& Elsevier]

Abstract: Behavioral and psychological symptoms of dementia (BPSD) include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite impairment. These symptoms have adverse consequences for patients and caregivers, such as greater impairment in activities of daily living, worsening quality of life and earlier institutionalization. While the etiology of BPSD has not been clearly delineated, studies assessing the benefits of acetylcholinesterase inhibitors on BPSD suggest that some of the neuropsychiatric symptoms of dementia such as agitation, apathy and psychosis may represent a specific central cholinergic deficiency syndrome. Biochemical and neuroimaging studies of BPSD in Alzheimer''s patients support these pharmacological data. This review discusses the literature describing the association between cholinergic deficiency and manifestations of BPSD. [Copyright &y& Elsevier]

Abstract: Numerous studies have demonstrated cognitive improvements resulting from the application of nicotine, especially in those tasks aimed at measuring attention. While the neuro-pharmacological relationship between nicotine and acetylcholine-driven attentional processes has been examined, studies tend to focus on the duration of time in which a subject can attend to a specific stimulus or series of stimuli rather than on the subjects’ adaptive attentional capabilities. The present study addresses the possibility that the cholinergic agonist nicotine could improve performance on a task testing the ability to shift attention between sensory modalities under both normal and pharmacologically impaired conditions. In a pilot set of experiments, we tested the effects of nicotine in a cross-modal experimental task designed to tax both the auditory and visual systems of male Sprague–Dawley rats. Nicotine (0.2mg/kg) significantly improved performance on both auditory and visual trials, under repetitive trial conditions, and significantly decreased overall response latency. For the primary study, we tested the effects of decreasing cholinergic neurotransmission by systemic administration of the muscarinic antagonist atropine. Atropine (12.5mg/kg) significantly impaired performance in auditory shift trials and perseverative trials, while significantly increasing the overall response latency. We then tested the effect of nicotine within the impaired model. Systemic administration of nicotine significantly improved performance in auditory and visual shift trials, while showing moderate improvements in response latency and perseverative trial conditions. These results indicate the potential therapeutic use of nicotine as a cognitive enhancer, as well as provide evidence for cholinergic system compensations. [Copyright &y& Elsevier]

Testosterone and ten of its metabolites were examined as inhibitors of butyrylcholinesterase. A significant enzyme inhibition activity (IC50 = 1.55 μM) was observed for androst-4-en-3,7-dione. The kinetic parameters of butyrylcholinesterase inhibition were determined and molecular docking was carried out in order to develop a better understanding of the inhibitor-enzyme interactions. The results showed that the inhibition was non-competitive, stabilized mainly by hydrogen bonds and hydrophobic interactions between the inhibitor and butyrylcholinesterase. [ABSTRACT FROM AUTHOR]

Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of age-related neurodegenerative diseases and their neuroanatomical–neurochemical underpinnings for purposes of translating this work toward first pharmacotherapies. This effort produced several notable findings that eventually received consensus support, which we have been asked to review. A discussion of these findings, in the context of issues and obstacles confronted and principles applied, might facilitate the development of even more effective models and treatments, not only for Alzheimer’s disease (AD) but for many other disorders involving cognitive deficits. Collectively, our research provided first evidence of the following: aged primates can be used as ‘models’ for human age-related neurodegenerative diseases; key cognitive deficits in early AD share important conceptual similarities to deficits in both aged monkeys as well as non-demented humans (e.g., age-associated memory impairment and mild cognitive impairment); pharmacological intervention can reduce age-related cognitive impairments in animals that are conceptually similar to those seen in human diseases, including AD; cholinergics would likely be the first approved therapeutics for AD; and that many other classes of drugs would not likely succeed. Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer''s disease (AD) is a progressive, neurodegenerative disease characterized by memory and cognitive loss, the formation of senile plaques containing amyloid-β (Aβ) peptide, degeneration of the cholinergic neurons and the development of neurofibrillary tangles. The build-up of Aβ is considered to be a central feature in the pathogenesis of AD. However, other critical molecular and neurochemical alterations too occur, such as a cholinergic dysfunction. As concerns the pathomechanism of the disease, both the amyloid cascade hypothesis and the cholinergic hypothesis of AD are widely accepted. This review surveys recent in vitro and in vivo experimental evidence relating to these two hypotheses. Bidirectional pathways linking them as regards the cholinergic neurotoxicity of Aβ and the regulatory mechanisms of cholinergic receptor activation or enzyme inhibition in the processing of the amyloid precursor protein are also discussed. Further work is warranted to elucidate the exact effects in the interactions between the cholinergic and amyloid hypotheses of the candidate drugs used in AD therapy. [Copyright &y& Elsevier]

The 'cholinergic hypothesis', based on the correlation of the reduction of cholinergic activity in Alzheimer's disease (AD) with cognition and memory, is currently the most widely-held view for AD. Drug treatments for AD focus mainly on inhibition of acetylcholinesterase (AChE), and to some extent butyrylcholinesterase (BChE). In addition to changes in AChE in AD, there is a rise in the level of the sister enzyme BChE. However, the role of the two cholinesterases is poorly understood in vivo. We characterized several proteins immunohistochemically in brain sections from AChE nullizygote (AChE-/-) and wild type AChE+/+ mice. Previous studies had shown that AChE-/- mouse tissues are devoid of AChE activity and that the overall cholinesterase activity is significantly decreased in the knockout group [16]. Despite the differences of cholinesterase activity, we found no significant structural alterations between the experimental groups. Immunohistochemical examination revealed no neuronal, dendritic, astrocytic, synaptic, microglial, and endothelial differences between AChE-/- and AChE+/+ mice. Similarly, the histochemical examination showed no morphologic alterations between AChE-/- and AChE+/+ mice. Our studies show that neither the absence of AChE nor the presence exclusively of BChE is associated with neuroglial and vascular pathology. [ABSTRACT FROM AUTHOR]

The article presents a discussion on the dimensions of the concept of Alzheimer's disease (AD) as a natural disease discerned by sophisticated medical scientific progress. It uses the views of Max Weber in questioning the empirical status of Alzheimer's disease (AD) and its prodromal derivative, mild cognitive impairment (MCI).

Presents a study which discussed the symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model. Definition of Alzheimer's disease; Effect of the treatment in the wild-type animals; Results of the study.

With an increased public awareness of Alzheimer’s disease (AD), the last two decades have witnessed an immense research effort directed towards discovering the cause of AD with the ultimate hope of developing safe and effective pharmacological treatments. Biochemical and histopathological changes of neurotransmitter markers in the brains of AD patients both at postmortem and neurosurgical cerebral biopsy have demonstrated an association between a decline in learning and memory, and a deficit in cholinergic and associated excitatory amino acid neurotransmission. These observations illustrate the selective neurotransmitter pathology of AD. Accordingly, although there is presently no ‘cure’ for AD, a large number of potential therapeutic strategies have emerged that are designed to correct the loss of cholinergic neurotransmission in AD. Such strategies include increasing acetylcholine synthesis, enhancing its presynaptic synthesis and/or release, potentiating its pre- or postsynaptic action, obstructing its metabolism, or by influencing the function of cholinergic neurones themselves by administration of nerve growth factor or by trans-synaptic modulation. Indeed, the cholinesterase (ChE) inhibitors have gained the most attention. Adverse events limited the usage of the first ChE inhibitors, but more recently introduced, well-tolerated compounds, for example donepezil, have confirmed efficacy in delaying the deterioration of symptoms of AD, a valuable treatment target considering the progressive nature of the disease. Other agents which affect the cholinergic system, directly or indirectly, that are in the early stages of development for the treatment of AD are also discussed. [ABSTRACT FROM AUTHOR]

BackgroundMemory and cognitive functions are known to decline with advancing age. Studies have suggested that this may be due to a decrease in cholinergic function in the brains of elderly people. This review aims to assess studies documented in the literature dealing with the ‘scopolamine model’ of dementia. MethodsSources included MedLine searches from the last 10 years (search for ‘scopolamine model’, ‘dementia’, ‘electroencephalogram’, ‘cognition’) and references from original and review articles. The aim was to include human and animal studies occupying the cholinergic hypothesis in cognitive dysfunction. Electroencephalographic (EEG) and cognition findings were considered. ResultsScopolamine influences delta, theta, alpha and beta activity in EEG and partially mimics the EEG changes found in patients with senile dementia or dementia of the Alzheimer type. Effects on different cognitive functions have been extensively documented. ConclusionScopolamine produces similar memory deficits seen in the elderly, but the drug cannot induce the full range of deficits seen in patients with Alzheimer's disease. Various aspects of memory were unaffected by scopolamine administration. Memory improvements in elderly subjects can be achieved after cholinergic stimulation. [ABSTRACT FROM AUTHOR]

• Lutein was encapsulated using GRAS components yielding nanometric particles. • Encapsulated lutein acted as an acetylcholinesterase inhibitor. • In silico docking studies showed how lutein interacts with the enzyme. • Nanoparticles with promising applicability in waterborne foodstuff. Lutein is a bioactive found in dark leafy vegetables that may be used as a nutraceutical agent in foodstuff and an inhibitor of key enzymes of the human body such as those involved in the cholinergic system. However, its high hydrophobicity leads to low bioavailability and must be overcome if lutein is to be added in foods. The objective of this study was to evaluate the influence of nanoencapsulated lutein in the activity of the acetylcholinesterase enzyme. The in vitro study was carried out using water in order to evaluate the impact of encapsulation on the hydrophilicity of lutein. In vitro assays showed that lutein, both free and nanoencapsulated, presented a mixed-type inhibition behavior, and encapsulated lutein was able to inhibit acetylcholinesterase activity even in an aqueous medium. Inhibition was also showed by the in silico docking results which show that lutein interacted with the pocket region of the enzyme. [ABSTRACT FROM AUTHOR]