AβPP-Overexpressing Transgenic Rat Model of Alzheimer's Disease Utilizing the Tg2576 Mouse Protocol

O’Hare, Eugene; Ardis, T.C.; Page, Deaglan; Scopes, D. I. C.; Kim, Eun-Mee

doi:10.3233/jad-130212

Cited by 3 publications

(3 citation statements)

References 41 publications

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“…Another Tg rat was developed using the Tg2576 mouse protocol. These rats exhibit cognitive deficits at 8–12 months, activated astrocytes in the brain, ThioS staining in the hippocampus and cortex, and elevated levels of Aβ 38 , Aβ 40 , and Aβ 42 [ 383 ]. Tg rats expressing the Swedish and Indiana APP mutations also exhibit elevated levels of these Aβ peptides in the CSF [ 384 ] as well as pre-plaque intracellular AβO-associated cognitive impairment [ 87 ].…”

Section: Trending Topics In Aβo Researchmentioning

confidence: 99%

The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

Cline

Bicca

Viola

et al. 2018

JAD

674

583

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The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer’s disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998). The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor. Over 4,000 articles concerning AβOs have been published since then, including more than 400 reviews. AβOs have been shown to accumulate in an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. As reviewed by Hayden and Teplow in 2013, the AβO hypothesis “has all but supplanted the amyloid cascade.” Despite the emerging understanding of the role played by AβOs in AD pathogenesis, AβOs have not yet received the clinical attention given to amyloid plaques, which have been at the core of major attempts at therapeutics and diagnostics but are no longer regarded as the most pathogenic form of Aβ. However, if the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term.

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Section: Trending Topics In Aβo Researchmentioning

confidence: 99%

The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

Cline

Bicca

Viola

et al. 2018

JAD

674

583

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“…Several transgenic rat models described in the literature show intracellular accumulation of Aβ but do not display amyloid plaque pathology (Echeverria et al ., ; Ruiz‐Opazo et al ., ; Folkesson et al ., ; Agca et al ., ). However, other models do present with progressive plaque pathology in addition to cognitive impairments (Liu et al ., ; Flood et al ., ; Leon et al ., ; Cohen et al ., ; O'Hare et al ., ). Modeling the loss of neurons seen in patients with AD has been less successful, and to date neuronal loss has only been reported in one rat transgenic model, line TgF344‐AD (Cohen et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer's disease

Heggland

Storkaas

Soligard

et al. 2015

Eur J of Neuroscience

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The main hallmarks of Alzheimer's disease (AD) are senile plaques, neurofibrillary tangles and neuronal death. The McGill-R-Thy1-APP rat is one of the few transgenic rat models of AD that displays progressive amyloid pathology. This study aimed to further characterise this rat model, focusing on the pathological changes in the hippocampal formation and the parahippocampal region. These structures, that are important for episodic memory and spatial navigation, are affected in the early stages of the disease. This study used unbiased stereology to investigate possible neuronal loss in the CA1, subiculum and entorhinal cortex of 18-month-old homozygous McGill-R-Thy1-APP rats, and also quantified the plaque load in all the areas of the hippocampal formation and parahippocampal region from 9 to 18 months old. A significant reduction of neurons at 18 months was only seen in the subiculum. The first plaque pathology was seen at 9 months in the subiculum. Although the quantified plaque load was variable between animals, the pattern of spatiotemporal progression was similar for all animals. The spread of plaque pathology mainly affected anatomically connected regions. Overall, the plaque pathology observed in the transgenic rats was similar to the early phases of amyloid beta (Aβ)-deposition described in human patients. The findings here thus indicate that the McGill-R-Thy1-APP rat could be a good model of the Aβ pathology in AD, but less so with respect to neuron loss.

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“…In contrast, pathological evidence shows the APOE e4 allele to be over-represented in Lewy body variants of AD patients; furthermore, coexisting Lewy body pathology has been found among AD patients 16,17. While previous studies show that APOE e4 alleles in AD were less likely to develop EPS,2 Iqbal et al reported that the presence of EPS may not only be useful in discriminating between AD and non-AD controls, but also exhibits a distinct distribution in a subgroup defined by late-onset AD with the presence of one or two APOE e4 alleles 18. Because the APOE e4 allele is also associated with higher frequencies of neuritic and diffuse amyloid plaques in AD patients, it is therefore reported in line with severity in AD pathological findings 20…”

Section: Discussionmentioning

confidence: 99%

<p>Apolipoprotein E e4 allele is associated with extrapyramidal symptoms in Alzheimer’s disease</p>

Chang

Chou

Lai

et al. 2019

NDT

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Background Extrapyramidal symptoms (EPS) are not uncommon in Alzheimer’s disease (AD). As apolipoprotein E(APOE) e4 allele is a major risk factor for late-onset AD, we intend to examine the association between APOE genotype and the development of EPS in AD. Method This study describes two hundred and fifty-five clinically diagnosed AD patients aged 72 to 80 years from 2010 to 2014. We reviewed the medical charts to determine the development of EPS. APOE genotypes were also confirmed. Results APOE e4 allele was detected in 74 patients (29%) and rigidity was among the most common EPS (61%). After adjusting the age, gender, baseline clinical dementia rating, we found AD patients carrying APOE e4 allele are more likely to develop EPS (OR: 4.515, p =0.033). Conclusion This study demonstrates the higher coexistence of EPS in AD patients with APOE e4 allele. Furthermore, the identification of APOE e4 allele in the development of EPS in AD patients supports the hypothesis that EPS may be partially attributed to AD pathology.

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AβPP-Overexpressing Transgenic Rat Model of Alzheimer's Disease Utilizing the Tg2576 Mouse Protocol

Cited by 3 publications

References 41 publications

The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer's disease

<p>Apolipoprotein E e4 allele is associated with extrapyramidal symptoms in Alzheimer’s disease</p>

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