Neurotransmitter enzyme abnormalities in senile dementia

Perry, Elaine K.; Gibson, Peter H.; Blessed, G.; Perry, Robert H.; Tomlinson, Bernard E.

doi:10.1016/0022-510x(77)90073-9

Cited by 661 publications

(113 citation statements)

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“…Previous studies have suggested that a decrease in brain bioenergetics may be a useful biomarker to predict disease decades before symptoms [33][34][35][36]. Decreases in mitochondrial bioenergetics, metabolic enzyme expression and activity, cerebral glucose metabolism, along with increased oxidative stress, Aβ deposits within mitochondria, and expression of ABAD are associated with the prodromal state of AD [34,[37][38][39][40][41][42].…”

Section: Current Strategies Targeting Mitochondria and Bioenergetics mentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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Section: Current Strategies Targeting Mitochondria and Bioenergetics mentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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“…Using tissue from this series, the amount of m l muscarinic receptor mRNA in temporal cortex was found to be influenced by terminal coma; that is, a significant correlation was observed between increasing duration of coma (1-336 h) and decreasing hybridization signal (Harrison et al,199 la). The activity of glutamate decarboxylase, an enzyme known to be impaired by hypoxia (Bowen et al, 1976;Perry et al, 1977), likely to accompany coma, correlated with the amount of mRNA. In contrast, other mRNAs do not show a relationship with AS in samples from the same series (Harrison et al, 1993 and authors' unpublished observations).…”

Section: Premortem Influences On Human Brain Rnamentioning

confidence: 99%

Pre‐and Postmortem Influences on Brain RNA

Barton

Pearson

Najlerahim

et al. 1993

Journal of Neurochemistry

243

142

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Many potentially valuable techniques for the understanding of human neurobiological and neuropathological processes require the use of RNA obtained from postmortem tissue. As with earlier neurochemical studies, there are two particular problems posed by such tissue in comparison with tissue from experimental animals. These are the postmortem interval and the condition of the patient prior to death, referred to as the agonal state. We review the nature and extent of the effects of postmortem interval and agonal state on RNA in brain tissue, with particular reference to the study of neuropsychiatric disorders. Perhaps surprisingly, postmortem interval has at most a modest effect on RNA. Abundant intact and biologically active RNA is present in tissue frozen 36 h or more after death. Postmortem interval does not account for the marked variability observed among human brains in all RNA parameters. Despite the overall stability of RNA after death, some evidence suggests that individual RNAs may undergo postmortem decay. Less attention has been paid to the effects of agonal state. The existing data indicate that events in the premortem period such as hypoxia and coma can affect the amount of some messenger RNAs. The nature of agonal state influences depends on the messenger RNA in question, though the basis for this selective vulnerability is unknown. No agonal state effect on overall RNA level or activity has been found. The data show that postmortem brain tissue can be used for RNA research. However, considerable attention must be paid to controlling for the influences of pre-and postmortem factors, especially when quantitative analyses are performed.

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“…The function of AChE is termination of nerve impulses at the cholinergic synapses through acetylcholine hydrolysis. Reduced amount of the acetylcholine, because of abnormal activity of сholine acetyltransferase [3,4], along with extracellular deposits of β-amyloid in senile plaques is associated with cognitive function impairment in patients with Alzheimer's disease [5,6]. According to the cholinergic hypothesis [7], consequences of the neurotransmitter deficit can be reduced by inhibition of AChE [5,8].…”

Section: Introductionmentioning

confidence: 99%

N-Phenacylthiazolium Salts as Inhibitors of Cholinesterases

et al. 2017

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Inhibition of acetylcholinesterase is considered as a promising approach for treatment of neurodegenerative disorders including Alzheimer's disease. In this study, we demonstrated that 5-substituted N-phenacylthiazolium derivatives are capable of inhibiting acetylcholinesterase and butyrylcholinesterase activities with IC50 values in the micromolar range. Some of the new thiazolium-based inhibitiors showed more than 10-fold selectivity for butyrylcholinesterase. Kinetic experiments and molecular docking were performed for understanding the inhibition mechanisms.________________________________________________________________________________

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Neurotransmitter enzyme abnormalities in senile dementia

Cited by 661 publications

References 36 publications

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Pre‐and Postmortem Influences on Brain RNA

N-Phenacylthiazolium Salts as Inhibitors of Cholinesterases

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