Glycogen and amyloid-beta: key players in the shift from neuronal hyperactivity to hypoactivity observed in Alzheimer′s disease?

Bass, Brittany; Upson, Sarah J.; Roy, Kamolika; Montgomery, Emily L; Jalonen, Tuula O.; Murray, Ian V.J.

doi:10.4103/1673-5374.160059

Cited by 20 publications

(8 citation statements)

References 27 publications

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“…Alternatively, this glutamatoxicity could be attributed to disinhibition of glutamatergic neurons resulting from the significantly reduced GABA levels. Reduced neuronal inhibition by GABA could explain the hippocampal hyperactivity observed in early AD [ 94 , 95 ], which may itself be a compensation for neuronal loss [ 94 - 96 ]. This is an interesting concept which ultimately suggests that in pre-AD stages, neuronal hyperactivity may lead to increased neuronal glutamate release.…”

Section: Discussionmentioning

confidence: 99%

“…We have used a similar approach to validate metabolic hypotheses in AD, as several lines of evidence implicate metabolic dysfunction in AD. First, the high energy requirement and limited energy stores of the brain [ 14 , 96 ] leads to neuronal dysfunction and death in AD because of the pathological reduction of glucose utilization and hypoperfusion [ 17 , 26 , 100 - 102 ]. Even though the AD brain may utilize lactate, pyruvate, glutamate, and glutamine, it is glucose which is the major energy source for ATP production [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…This reduced glucose utilization may be a result of insulin resistance in the brain (type 3 diabetes) [ 107 , 108 ], or alterations to vascular flow or glucose uptake by astrocytes [ 109 ]. Second and alternatively, there are two concurrent processes taking place: loss of metabolically active neurons [ 26 ] and neuronal hyperactivity [ 96 , 110 ]. An overall decrease in glucose utilization with increased disease severity [ 26 ] may, therefore, reflect neuronal loss, while the elevated lactate reflects increased synaptic activity [ 111 ] and thus also glycolytic flux.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Metabolic and Synaptic Dysfunction Hypotheses of Alzheimer's Disease (AD): A Meta-Analysis of CSF Markers

Manyevitch

Protas

Scarpiello

et al. 2018

CAR

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Background:Alzheimer’s disease (AD) is currently incurable and a majority of investigational drugs have failed clinical trials. One explanation for this failure may be the invalidity of hypotheses focus-ing on amyloid to explain AD pathogenesis. Recently, hypotheses which are centered on synaptic and met-abolic dysfunction are increasingly implicated in AD.Objective:Evaluate AD hypotheses by comparing neurotransmitter and metabolite marker concentrations in normal versus AD CSF.Methods:Meta-analysis allows for statistical comparison of pooled, existing cerebrospinal fluid (CSF) marker data extracted from multiple publications, to obtain a more reliable estimate of concentrations. This method also provides a unique opportunity to rapidly validate AD hypotheses using the resulting CSF con-centration data. Hubmed, Pubmed and Google Scholar were comprehensively searched for published Eng-lish articles, without date restrictions, for the keywords “AD”, “CSF”, and “human” plus markers selected for synaptic and metabolic pathways. Synaptic markers were acetylcholine, gamma-aminobutyric acid (GABA), glutamine, and glycine. Metabolic markers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies that measured markers in AD and controls (Ctl), provided means, standard er-rors/deviation, and subject numbers were included. Data were extracted by six authors and reviewed by two others for accuracy. Data were pooled using ratio of means (RoM of AD/Ctl) and random effects meta-analysis using Cochrane Collaboration’s Review Manager software.Results:Of the 435 identified publications, after exclusion and removal of duplicates, 35 articles were in-cluded comprising a total of 605 AD patients and 585 controls. The following markers of synaptic and met-abolic pathways were significantly changed in AD/controls: acetylcholine (RoM 0.36, 95% CI 0.24-0.53, p<0.00001), GABA (0.74, 0.58-0.94, p<0.01), pyruvate (0.48, 0.24-0.94, p=0.03), glutathione (1.11, 1.01-1.21, p=0.03), alanine (1.10, 0.98-1.23, p=0.09), and lower levels of significance for lactate (1.2, 1.00-1.47, p=0.05). Of note, CSF glucose and glutamate levels in AD were not significantly different than that of the controls.Conclusion:This study provides proof of concept for the use of meta-analysis validation of AD hypothe-ses, specifically via robust evidence for the cholinergic hypothesis of AD. Our data disagree with the other synaptic hypotheses of glutamate excitotoxicity and GABAergic resistance to neurodegeneration, given ob-served unchanged glutamate levels and decreased GABA levels. With regards to metabolic hypotheses, the data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and anaple-rosis of the tricarboxylic acid cycle using glutamate. Future applications of meta-analysis indicate the pos-sibility of further in silico evaluation and generation of novel hypotheses in the AD field.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Evaluation of Metabolic and Synaptic Dysfunction Hypotheses of Alzheimer's Disease (AD): A Meta-Analysis of CSF Markers

Manyevitch

Protas

Scarpiello

et al. 2018

CAR

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“…To our surprise, even though oligomer Aβ 42 stimulated SH‐SY5Y cells showed lowered α‐amylase concentration, glycogen load was equally lowered in these cells. Of note, patients with AD show both reduced glycogen load (Bass et al, 2015 ) and increased glycogen synthesis‐regulating GSK3beta (Reddy, 2013 ) which is shown to lower production of glycogen (Bass et al, 2015 ; Beurel et al, 2015 ). The Aβ‐induced reduction of both glycogen and α‐amylase in neurons suggests that there is a doubled impact on glycogen metabolism, that is, both a reduction in degradation and formation of glycogen.…”

Section: Discussionmentioning

confidence: 99%

Neuronal α‐amylase is important for neuronal activity and glycogenolysis and reduces in presence of amyloid beta pathology

et al. 2021

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Recent studies indicate a crucial role for neuronal glycogen storage and degradation in memory formation. We have previously identified alpha‐amylase (α‐amylase), a glycogen degradation enzyme, located within synaptic‐like structures in CA1 pyramidal neurons and shown that individuals with a high copy number variation of α‐amylase perform better on the episodic memory test. We reported that neuronal α‐amylase was absent in patients with Alzheimer's disease (AD) and that this loss corresponded to increased AD pathology. In the current study, we verified these findings in a larger patient cohort and determined a similar reduction in α‐amylase immunoreactivity in the molecular layer of hippocampus in AD patients. Next, we demonstrated reduced α‐amylase concentrations in oligomer amyloid beta 42 (Aβ42) stimulated SH‐SY5Y cells and neurons derived from human‐induced pluripotent stem cells (hiPSC) with PSEN1 mutation. Reduction of α‐amylase production and activity, induced by siRNA and α‐amylase inhibitor Tendamistat, respectively, was further shown to enhance glycogen load in SH‐SY5Y cells. Both oligomer Aβ42 stimulated SH‐SY5Y cells and hiPSC neurons with PSEN1 mutation showed, however, reduced load of glycogen. Finally, we demonstrate the presence of α‐amylase within synapses of isolated primary neurons and show that inhibition of α‐amylase activity with Tendamistat alters neuronal activity measured by calcium imaging. In view of these findings, we hypothesize that α‐amylase has a glycogen degrading function within synapses, potentially important in memory formation. Hence, a loss of α‐amylase, which can be induced by Aβ pathology, may in part underlie the disrupted memory formation seen in AD patients.

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“…Finally, one of the latest manifestations of AD is hypoactivity, which is due, according to Bass and colleagues [ 83 ], to a combination of homeostatic alterations and A β plaque proliferation. As mentioned in Introduction, our computational model is not able to simulate the A β plaques proliferation, being only able to predict events until reaching the initial hypermetabolic stage that is associated with persistent neural oscillations.…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s Disease as a Result of Stimulus Reduction in a GABA-A-Deficient Brain: A Neurocomputational Model

Aguiar-Furucho

Peláez

2020

Neural Plasticity

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Several research studies point to the fact that sensory and cognitive reductions like cataracts, deafness, macular degeneration, or even lack of activity after job retirement, precede the onset of Alzheimer’s disease. To simulate Alzheimer’s disease earlier stages, which manifest in sensory cortices, we used a computational model of the koniocortex that is the first cortical stage processing sensory information. The architecture and physiology of the modeled koniocortex resemble those of its cerebral counterpart being capable of continuous learning. This model allows one to analyze the initial phases of Alzheimer’s disease by “aging” the artificial koniocortex through synaptic pruning, by the modification of acetylcholine and GABA-A signaling, and by reducing sensory stimuli, among other processes. The computational model shows that during aging, a GABA-A deficit followed by a reduction in sensory stimuli leads to a dysregulation of neural excitability, which in the biological brain is associated with hypermetabolism, one of the earliest symptoms of Alzheimer’s disease.

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Glycogen and amyloid-beta: key players in the shift from neuronal hyperactivity to hypoactivity observed in Alzheimer′s disease?

Cited by 20 publications

References 27 publications

Evaluation of Metabolic and Synaptic Dysfunction Hypotheses of Alzheimer's Disease (AD): A Meta-Analysis of CSF Markers

Evaluation of Metabolic and Synaptic Dysfunction Hypotheses of Alzheimer's Disease (AD): A Meta-Analysis of CSF Markers

Neuronal α‐amylase is important for neuronal activity and glycogenolysis and reduces in presence of amyloid beta pathology

Alzheimer’s Disease as a Result of Stimulus Reduction in a GABA-A-Deficient Brain: A Neurocomputational Model

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