Subtle learning and memory impairment in an idiopathic rat model of Alzheimer's disease utilizing cholinergic depletions and β-amyloid

Deibel, Scott H.; Weishaupt, Nina; Regis, Aaron; Hong, Nancy S.; Keeley, Robin J.; Balog, R.J.; Bye, Cameron M.; Himmler, Stephanie M.; Whitehead, Shawn N.; McDonald, Robert J.

doi:10.1016/j.brainres.2016.05.033

Cited by 14 publications

(6 citation statements)

References 80 publications

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“…However, no remarkable differences of 5-hydroxytryptamine, γ-aminobutyric acid, glutamic acid and aspartic acid between the two groups were observed. Relative reports of neurotransmitters in brain tissues of AD patients revealed decreased concentrations of acetylcholine, norepinephrine and glutamic acid [9,24]. Our results were basically in accordance with the previous literatures.…”

Section: Discussionsupporting

confidence: 93%

Rapid HPLC-ESI-MS/MS Analysis of Neurotransmitters in the Brain Tissue of Alzheimer’s Disease Rats before and after Oral Administration of Xanthoceras sorbifolia Bunge

Sun

2018

Molecules

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In order to explore the potential therapeutic effect of Xanthoceras sorbifolia Bunge. against Alzheimer’s disease, an HPLC-MS/MS method has been developed and validated for simultaneous determination in rat brain of eight neurotransmitters, including dopamine, norepinephrine, 5-hydroxy-tryptamine, acetylcholine, l-tryptophan, γ-aminobutyric acid, glutamic acid and aspartic acid with a simple protein precipitation method for sample pre-treatment. The brain samples were separated on a polar functional group embedded column, then detected on a 4000 QTrap HPLC-MS/MS system equipped with a turbo ion spray source in positive ion and multiple reaction monitoring mode. The method was fully validated to be precise and accurate within the linearity range of the assay, and successfully applied to compare the neurotransmitters in the rat brain from four groups of normal, Alzheimer’s disease, and the oral administration group of X. sorbifolia extract and huperzine. The results indicated that brain levels of dopamine, norepinephrine and acetyl choline all decreased in the AD rats, while l-tryptophan showed an opposite trend. After administration of the Xanthoceras sorbifolia extract and huperzine, the level of acetyl choline and tryptophan returned to normal. Combination of the metabolic analysis, the results indicated that acetyl choline and l-tryptophan could be employed as therapy biomarkers for AD, and the results shown that the crude extract of the husks from Xanthoceras sorbifolia might ameliorate the impairment of learning and memory in the Alzheimer’s disease animal model with similar function of AchEI as huperzine. The established method would provide an innovative and effective way for the discovery of novel drug against Alzheimer’s disease, and stimulate a theoretical basis for the design and development of new drugs.

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Section: Discussionsupporting

confidence: 93%

Rapid HPLC-ESI-MS/MS Analysis of Neurotransmitters in the Brain Tissue of Alzheimer’s Disease Rats before and after Oral Administration of Xanthoceras sorbifolia Bunge

Sun

2018

Molecules

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“…In the retina of a transgenic mouse model of AD (Tg-SwDI), specific cholinergic cell loss together with reactive gliosis was found [ 108 ]. Cholinergic dysfunction induced by A β is established at distinct levels: neurodegeneration of cholinergic cells [ 110 ], ACh depletion [ 111 ], impaired ACh release [ 112 ], and finally A β -induced impairment of muscarinic [ 113 ] and nicotinic acetylcholine receptors (e.g., α 7-nAChR) [ 114 ], as well as associated effectors (e.g., potassium voltage-gated channels, KCNQ) [ 115 – 117 ]. In older animal models, downregulation of α 4, α 7, α 9, and α 10 nAChR, and m4 and m5 muscarinic acetylcholine receptor (mAChR) subunits, was found.…”

Section: Functional and Pathological Findings In The Visual Systemmentioning

confidence: 99%

Visual Features in Alzheimer’s Disease: From Basic Mechanisms to Clinical Overview

et al. 2018

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Alzheimer's disease (AD) is the leading cause of dementia worldwide. It compromises patients' daily activities owing to progressive cognitive deterioration, which has elevated direct and indirect costs. Although AD has several risk factors, aging is considered the most important. Unfortunately, clinical diagnosis is usually performed at an advanced disease stage when dementia is established, making implementation of successful therapeutic interventions difficult. Current biomarkers tend to be expensive, insufficient, or invasive, raising the need for novel, improved tools aimed at early disease detection. AD is characterized by brain atrophy due to neuronal and synaptic loss, extracellular amyloid plaques composed of amyloid-beta peptide (Aβ), and neurofibrillary tangles of hyperphosphorylated tau protein. The visual system and central nervous system share many functional components. Thus, it is plausible that damage induced by Aβ, tau, and neuroinflammation may be observed in visual components such as the retina, even at an early disease stage. This underscores the importance of implementing ophthalmological examinations, less invasive and expensive than other biomarkers, as useful measures to assess disease progression and severity in individuals with or at risk of AD. Here, we review functional and morphological changes of the retina and visual pathway in AD from pathophysiological and clinical perspectives.

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“…This suggests some form of synergy between processes connecting brain immunity, neuroplasticity, and neuronal survival. However, other studies involving cholinergic depletion and optogenetic stimulation did not result in improved neuroplasticity and sometimes even decreased cognitive performance and increased neuroinflammation (Deibel et al, 2016;Iaccarino et al, 2016). Effects on Aβ and tau neuropathology were mixed, with some studies showing reduced burden (Hao et al, 2011;Chen et al, 2012;Wu et al, 2013;Iaccarino et al, 2016;Ahmad et al, 2017;Martorell et al, 2019), while others reported no effect (Bachstetter et al, 2012;Deibel et al, 2016;Liang et al, 2019), and these changes did not always correspond to the studies that showed improved synaptic plasticity.…”

Section: Early Neuroplasticity Loss In Ad and In Mouse Models Is Revementioning

confidence: 99%

“…The majority of studies seeking to improve synaptic plasticity have been conducted using either transgenic rodent models of Aβ deposition or injection models of Aβ (Hao et al, 2011;Bachstetter et al, 2012;Chen et al, 2012;Duffy and Hölscher, 2013;Wu et al, 2013;Deibel et al, 2016;Iaccarino et al, 2016;Ahmad et al, 2017;Wilkaniec et al, 2018;Liang et al, 2019;Martorell et al, 2019), while very few have been executed in tau transgenic models (Martorell et al, 2019), leading to a relative lack of understanding of tau-related abnormalities in neuroplasticity and glial plasticity. In wild type mice or human APP transgenic mice, various inhibitors, agonists, or small molecules as well as brain stimulation and environmental enrichment have been tested ( Supplementary Table S1).…”

Section: Early Neuroplasticity Loss In Ad and In Mouse Models Is Revementioning

confidence: 99%

Tau-Mediated Dysregulation of Neuroplasticity and Glial Plasticity

Koller

Chakrabarty

2020

Front. Mol. Neurosci.

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The inability of individual neurons to compensate for aging-related damage leads to a gradual loss of functional plasticity in the brain accompanied by progressive impairment in learning and memory. Whereas this loss in neuroplasticity is gradual during normal aging, in neurodegenerative diseases such as Alzheimer's disease (AD), this loss is accelerated dramatically, leading to the incapacitation of patients within a decade of onset of cognitive symptoms. The mechanisms that underlie this accelerated loss of neuroplasticity in AD are still not completely understood. While the progressively increasing proteinopathy burden, such as amyloid β (Aβ) plaques and tau tangles, definitely contribute directly to a neuron's functional demise, the role of non-neuronal cells in controlling neuroplasticity is slowly being recognized as another major factor. These non-neuronal cells include astrocytes, microglia, and oligodendrocytes, which through regulating brain homeostasis, structural stability, and trophic support, play a key role in maintaining normal functioning and resilience of the neuronal network. It is believed that chronic signaling from these cells affects the homeostatic network of neuronal and non-neuronal cells to an extent to destabilize this harmonious milieu in neurodegenerative diseases like AD. Here, we will examine the experimental evidence regarding the direct and indirect pathways through which astrocytes and microglia can alter brain plasticity in AD, specifically as they relate to the development and progression of tauopathy. In this review article, we describe the concepts of neuroplasticity and glial plasticity in healthy aging, delineate possible mechanisms underlying tau-induced plasticity dysfunction, and discuss current clinical trials as well as future disease-modifying approaches.

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Subtle learning and memory impairment in an idiopathic rat model of Alzheimer's disease utilizing cholinergic depletions and β-amyloid

Cited by 14 publications

References 80 publications

Rapid HPLC-ESI-MS/MS Analysis of Neurotransmitters in the Brain Tissue of Alzheimer’s Disease Rats before and after Oral Administration of Xanthoceras sorbifolia Bunge

Rapid HPLC-ESI-MS/MS Analysis of Neurotransmitters in the Brain Tissue of Alzheimer’s Disease Rats before and after Oral Administration of Xanthoceras sorbifolia Bunge

Visual Features in Alzheimer’s Disease: From Basic Mechanisms to Clinical Overview

Tau-Mediated Dysregulation of Neuroplasticity and Glial Plasticity

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