Lesion-Induced Vertebrate Models of Alzheimer Dementia

Toledano, A; Álvarez, María Isabel Calvo

doi:10.1007/978-1-60761-898-0_16

Cited by 7 publications

(6 citation statements)

References 211 publications

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“…Focal lesions are especially directed at the nucleus basalis magnocellularis (Lescaudron and Stein, 1999; Vale‐Martínez et al ., 2002), the rodent analogue of the human nucleus basalis of Meynert, the septal area (Mulder et al ., 2005), or consist of fimbria/fornix transection leading to septo‐hippocampal cholinergic denervation (He et al ., 1992; Alonso et al ., 1996). Lesioning can be achieved by surgical or electrolytical procedures, and intraparenchymal or intracerebroventricular microinjections of neurotoxic substances, such as quinolic, kainic, N‐methyl‐D‐aspartic, ibotenic and quisqualic acids, the cholinotoxin AF64, and the immunotoxin 192 IgG‐saporin (for review, see Toledana and Álvarez, 2010). These models increase our understanding of the role of cholinergic innervations in the aetiology and treatment of cognitive disorders.…”

Section: Pharmacological Chemical and Lesion‐induced Rodent Modelsmentioning

confidence: 99%

“…age at induction) and maintenance (e.g. housing conditions), the model protocol, including the location and extent of the lesion and whether a unilateral or bilateral lesion is opted for, the lesion‐inducing agent, the type and concentration of toxin used, and even the morphological, histochemical, biochemical and cognitive methods used to phenotype the model (for review, see Toledana and Álvarez, 2010).…”

Section: Pharmacological Chemical and Lesion‐induced Rodent Modelsmentioning

confidence: 99%

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Animal models in the drug discovery pipeline for Alzheimer's disease

Dam

Deyn

2011

British J Pharmacology

200

137

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With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease-modifying compounds has become even more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease-modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease-related research as valid models enable the appraisal of early pathological processes -which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence-accelerated mice, chemical and lesion-induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions. LINKED ARTICLESThis article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10. 1111/bph.2011.164.issue-4 Abbreviations Ab, amyloid-b; AD, Alzheimer's disease; APP, amyloid precursor protein; BACE1, b-site APP-cleaving enzyme 1; BPSD, behavioural and psychological signs and symptoms of dementia; EGFP, enhanced green fluorescent protein; GSK-3b, glycogen synthase kinase 3b; NFT, neurofibrillary tangle; PSEN, presenilin; SAM, senescence-accelerated mouse; SAMP, SAM-prone; TILLING, targeted induced local lesions in genomes; ZFN, zinc finger nuclease IntroductionAs the prototype of cortical dementias, Alzheimer's disease (AD) presents with prominent cognitive deficits. Initially, patients display limited forgetfulness with disruption of memory imprinting, which evolves to short-term memory disruption and, eventually, to long-term memory deficits. At more advanced stages, patients show executive dysfunctioning leading to advanced helplessness. Besides cognitive deterioration, patients display behavioural and psychological signs and symptoms of dementia (BPSD). BPSD is an umbrella term that embraces a heterogeneous group of noncognitive symptoms and behaviours, including paranoid and delusional ideation, hallucinations, activity disturbances, BJPBritish Journal of Pharmacology...

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Section: Pharmacological Chemical and Lesion‐induced Rodent Modelsmentioning

confidence: 99%

Section: Pharmacological Chemical and Lesion‐induced Rodent Modelsmentioning

confidence: 99%

Animal models in the drug discovery pipeline for Alzheimer's disease

Dam

Deyn

2011

British J Pharmacology

200

137

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“…The earliest animal models of AD were created by disrupting the cholinergic system in various mammalian species using surgical methods, neurotoxins, immunotoxins, or pharmacological methods. The species targeted included mice and rats [ 41 ], rabbits [ 42 ], and monkeys such as the marmoset and crab eating macaque [ 43 , 44 ]. The cholinergic system in the basal forebrain degenerates early in the course of AD [ 45 , 46 ].…”

Section: Modelling Ad In Animalsmentioning

confidence: 99%

“…The cholinergic system in the basal forebrain degenerates early in the course of AD [ 45 , 46 ]. These models replicated some of the symptoms of AD such as memory impairments, and were helpful for testing the efficacy of cholinesterase inhibitors, which can offer some symptomatic relief early in the course of AD [ 41 ]. These models, of course, did not develop plaques or tangles, nor did they represent the progression of the complex biochemical and cellular-level changes in AD [ 47 ].…”

Section: Modelling Ad In Animalsmentioning

confidence: 99%

A Review of the Current Mammalian Models of Alzheimer’s Disease and Challenges That Need to Be Overcome

Mckean

Handley

Snell

2021

IJMS

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Alzheimer’s disease (AD) is one of the looming health crises of the near future. Increasing lifespans and better medical treatment for other conditions mean that the prevalence of this disease is expected to triple by 2050. The impact of AD includes both the large toll on individuals and their families as well as a large financial cost to society. So far, we have no way to prevent, slow, or cure the disease. Current medications can only alleviate some of the symptoms temporarily. Many animal models of AD have been created, with the first transgenic mouse model in 1995. Mouse models have been beset by challenges, and no mouse model fully captures the symptomatology of AD without multiple genetic mutations and/or transgenes, some of which have never been implicated in human AD. Over 25 years later, many mouse models have been given an AD-like disease and then ‘cured’ in the lab, only for the treatments to fail in clinical trials. This review argues that small animal models are insufficient for modelling complex disorders such as AD. In order to find effective treatments for AD, we need to create large animal models with brains and lifespan that are closer to humans, and underlying genetics that already predispose them to AD-like phenotypes.

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“…In particular, in brains of AD patients, dramatic glial reactivity was observed along with amyloid deposition, tangle formation, and loss/dysfunction of cholinergic neurons in the basal forebrain (Monzon‐Mayor et al, ). Lesioning of the NB in experimental animals has often been used for elucidating the role of central cholinergic neurotransmission and pathogenesis of human disorders (such as AD) that are accompanied by degeneration of cortical cholinergic neurons (Arendash et al, ; Anezaki et al, ; Monzon‐Mayor et al, ; Toledano and Alvarez, ; Swarowsky et al, ). Moreover, it is well known that there is a close relationship between amyloid deposits and normal and reactive glial cells, implying a role of glial involvement in amyloid precursor protein mismetabolism.…”

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confidence: 99%

Glial response in the rat models of functionally distinct cholinergic neuronal denervations

Bataveljić

Petrović

Lazic

et al. 2014

J of Neuroscience Research

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Alzheimer's disease (AD) involves selective loss of basal forebrain cholinergic neurons, particularly in the nucleus basalis (NB). Similarly, Parkinson's disease (PD) might involve the selective loss of pedunculopontine tegmental nucleus (PPT) cholinergic neurons. Therefore, lesions of these functionally distinct cholinergic centers in rats might serve as models of AD and PD cholinergic neuropathologies. Our previous articles described dissimilar sleep/wake-state disorders in rat models of AD and PD cholinergic neuropathologies. This study further examines astroglial and microglial responses as underlying pathologies in these distinct sleep disorders. Unilateral lesions of the NB or the PPT were induced with rats under ketamine/diazepam anesthesia (50 mg/kg i.p.) by using stereotaxically guided microinfusion of the excitotoxin ibotenic acid (IBO). Twenty-one days after the lesion, loss of cholinergic neurons was quantified by nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry, and the astroglial and microglial responses were quantified by glia fibrillary acidic protein/OX42 immunohistochemistry. This study demonstrates, for the first time, the anatomofunctionally related astroglial response following unilateral excitotoxic PPT cholinergic neuronal lesion. Whereas IBO NB and PPT lesions similarly enhanced local astroglial and microglial responses, astrogliosis in the PPT was followed by a remote astrogliosis within the ipslilateral NB. Conversely, there was no microglial response within the NB after PPT lesions. Our results reveal the rostrorostral PPT-NB astrogliosis after denervation of cholinergic neurons in the PPT. This hierarchically and anatomofunctionally guided PPT-NB astrogliosis emerged following cholinergic neuronal loss greater than 17% throughout the overall rostrocaudal PPT dimension.

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Lesion-Induced Vertebrate Models of Alzheimer Dementia

Cited by 7 publications

References 211 publications

Animal models in the drug discovery pipeline for Alzheimer's disease

Animal models in the drug discovery pipeline for Alzheimer's disease

A Review of the Current Mammalian Models of Alzheimer’s Disease and Challenges That Need to Be Overcome

Glial response in the rat models of functionally distinct cholinergic neuronal denervations

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