Lesions and Dysfunctions of the Nucleus Basalis as Alzheimers Disease Models: General and Critical Overview and Analysis of the Long-Term Changes in Several Excitotoxic Models

Toledano, A; Mi, Alvarez

doi:10.2174/1567205043332117

Cited by 37 publications

(35 citation statements)

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“…56 Hence, substantial efforts were invested in producing relevant animal models of AD (for a comprehensive review of literature, see references 57,58 ). Initial models of AD were simply normal aged animals, 59,60 which showed cholinergic involution associated (in monkeys) with b-amyloid deposition.…”

Section: Animal Models Of Admentioning

confidence: 99%

“…Among these, the most relevant were the rodent models with lesions in the nucleus basalis magnocellularis (nbm) that is the equivalent of the nucleus of Meynert in humans. 56,63,64 These models offered the possibility to investigate the differences in structure, function and behaviour of the cholinergic systems in young and aged animals. 63,64 The majority of these models, however, were created by using non-selective excitotoxic toxins such as NMDA, ibotenic acid, quisqualic acid and certain alkaloid substances.…”

Section: Animal Models Of Admentioning

confidence: 99%

“…63,64 The majority of these models, however, were created by using non-selective excitotoxic toxins such as NMDA, ibotenic acid, quisqualic acid and certain alkaloid substances. 56 More refined lesion models used more selective and specific toxins that affected only cholinergic neurones in the relevant areas, such as septum, nbm and the diagonal band of Broca, but preserved non-cholinergic neurones. 56,65 These models were produced by using AF64A cholinotoxin, which binds to the high affinity choline uptake system, and 192 IgG-saporin that binds selectively and irreversibly to low affinity nerve growth factor receptor interrupting cholinergic neuronal protein synthesis.…”

Section: Animal Models Of Admentioning

confidence: 99%

“…56 More refined lesion models used more selective and specific toxins that affected only cholinergic neurones in the relevant areas, such as septum, nbm and the diagonal band of Broca, but preserved non-cholinergic neurones. 56,65 These models were produced by using AF64A cholinotoxin, which binds to the high affinity choline uptake system, and 192 IgG-saporin that binds selectively and irreversibly to low affinity nerve growth factor receptor interrupting cholinergic neuronal protein synthesis. Both these interventions lead to selective impairment and death of cholinergic neurones.…”

Section: Animal Models Of Admentioning

confidence: 99%

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Astroglia in dementia and Alzheimer's disease

et al. 2008

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Astrocytes, the most numerous cells in the brain, weave the canvas of the grey matter and act as the main element of the homoeostatic system of the brain. They shape the microarchitecture of the brain, form neuronal-glial-vascular units, regulate the blood-brain barrier, control microenvirionment of the central nervous system and defend nervous system against multitude of insults. Here, we overview the pathological potential of astroglia in various forms of dementias, and hypothesise that both atrophy of astroglia and reactive hypertrophic astrogliosis may develop in parallel during neurodegenerative processes resulting in dementia. We also show that in the transgenic model of Alzheimer's disease, reactive hypertrophic astrocytes surround the neuritic plaques, whereas throughout the brain parenchyma astroglial cells undergo atrophy. Astroglial atrophy may account for early changes in synaptic plasticity and cognitive impairments, which develop before gross neurodegenerative alterations.

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Section: Animal Models Of Admentioning

confidence: 99%

Section: Animal Models Of Admentioning

confidence: 99%

Section: Animal Models Of Admentioning

confidence: 99%

Section: Animal Models Of Admentioning

confidence: 99%

See 2 more Smart Citations

Astroglia in dementia and Alzheimer's disease

et al. 2008

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“…For example, denervation of cholinergic fibers in the brain results in severe impairment of learning and memory (Toledano and Alvarez 2004). Genetic disruption of the two classes of acetylcholine receptors, muscarinic and nicotinic, also impairs cognition, learning, and memory (Champtiaux and Changeux 2004;Wess 2004).…”

mentioning

confidence: 99%

Nicotine induces dendritic spine remodeling in cultured hippocampal neurons

Oda

Nakagomi

Uejima

et al. 2013

Journal of Neurochemistry

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Cholinergic neurons in the CNS are involved in synaptic plasticity and cognition. Both muscarinic and nicotinic acetylcholine receptors (nAChRs) influence plasticity and cognitive function. The mechanism underlying nAChR-induced plasticity, however, has remained elusive. Here, we demonstrate morphological changes in dendritic spines following activation of a4b2* nAChRs, which are expressed on glutamatergic presynaptic termini of cultured hippocampal neurons. Exposure of the neurons to nicotine resulted in a lateral enlargement of spine heads. This was abolished by dihydro-b-erythroidine, an antagonist of a4b2* nAChRs, but not by a-bungarotoxin, an antagonist of a7 nAChRs. Tetanus toxin or a mixture of 2-amino-5-phosphonovaleric acid and 6-cyano-7-nitroquinoxaline-2,3-dione, antagonists of NMDA-and AMPA-type glutamate receptors, blocked the nicotine-induced spine remodeling. In addition, nicotine exerted full spine-enlarging response in the post-synaptic neuron whose b2 nAChR expression was knocked down. Finally, pre-treatment with nicotine enhanced the Ca 2+ -response of the neurons to glutamate. These data suggest that nicotine influences the activity of glutamatergic neurotransmission through the activation of pre-synaptic a4b2 nAChRs, resulting in the modulation of spinal architecture and responsiveness. The present findings may represent one of the cellular mechanisms underlying cholinergic tuning of brain function.

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Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

2019

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The only drugs currently approved for the treatment of Alzheimer's Disease (AD) are four acetylcholinesterase inhibitors and the NMDA antagonist memantine. Apart from these drugs, which have minimal to no clinical benefit, the 40‐year search for effective therapeutics to treat AD has resulted in a clinical failure rate of 100% not only for compounds that prevent brain amyloid deposition or remove existing amyloid plaques but also those acting by a variety of other putative disease‐associated mechanisms. This indicates that the preclinical data generated from current AD targets to support the selection, optimization, and translation of new chemical entities (NCEs) and biologics to clinical trials is seriously compromised. While many of these failures reflect flawed hypotheses or a lack of adequate characterization of the preclinical pharmacodynamic and pharmacokinetic (PD/PK) properties of lead NCEs—including their bioavailability and toxicity—the conceptualization, validation, and interrogation of the current animal models of AD represent key limitations. The overwhelming majority of these AD models are transgenic, based on aspects of the amyloid hypothesis and the genetics of the familial form of the disease. As a result, these generally lack construct and predictive validity for the sporadic form of the human disease. The 170 or so transgenic models, perhaps the largest number ever focused on a single disease, use rodents, mainly mice, and in addition to amyloid also address aspects of tau causality with more complex multigene models including other presumed causative factors together with amyloid. This overview discusses the current animal models of AD in the context of both the controversies surrounding the causative role of amyloid in the disease and the need to develop validated models of cognitive function/dysfunction that more appropriately reflect the phenotype(s) of human aged‐related dementias. © 2019 by John Wiley & Sons, Inc.

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Lesions and Dysfunctions of the Nucleus Basalis as Alzheimers Disease Models: General and Critical Overview and Analysis of the Long-Term Changes in Several Excitotoxic Models

Cited by 37 publications

References 0 publications

Astroglia in dementia and Alzheimer's disease

Astroglia in dementia and Alzheimer's disease

Nicotine induces dendritic spine remodeling in cultured hippocampal neurons

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

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