Transgenic mouse models of Alzheimer's disease: How useful have they been for therapeutic development?

Duff, Karen; Suleman, Faraha

doi:10.1093/bfgp/3.1.47

Cited by 92 publications

(56 citation statements)

References 83 publications

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“…Neuronal loss in neocortex and hippocampus are closely associated with the process of neurofibrillary degeneration [2]. Different transgenic mouse models of Alzheimer's neuropathology have been created to advance the understanding of the disease and development of treatments [3]. The rTg4510 mouse model is characterized by conditional overexpression of hyperphosphorylated human P301L mutant tau and profound neurofibrillary pathology, neurodegeneration and behavioral impairment [4].…”

Section: Introductionmentioning

confidence: 99%

Characterizing the Regional Structural Difference of the Brain between Tau Transgenic (rTg4510) and Wild-Type Mice Using MRI

Xie

Yang

Stephenson

et al. 2010

Medical Image Computing and Computer-Assisted Intervention – MICCAI 2010

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Abstract. rTg4510 transgenic mouse model demonstrates features resembling Alzheimer's disease including neurofibrillary degeneration and progressive neuronal loss. We investigated the volumetric differences of brain structures between transgenic and wild-type mice using MR images of fourteen 5.5 month old female mice. Tensor-based morphometry and atlas-based segmentation were applied to MRI images. Severe atrophy of hippocampus and neocortex as well as ventricular dilatation were observed in the transgenic mice. These findings were confirmed by histopathologic evaluation of the same mice. The results suggest that MRI should be useful for evaluating disease-modifying therapies for Alzheimer's disease in the rTg4510 model and comparing treatment responses in mice and humans.

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Section: Introductionmentioning

confidence: 99%

Characterizing the Regional Structural Difference of the Brain between Tau Transgenic (rTg4510) and Wild-Type Mice Using MRI

Xie

Yang

Stephenson

et al. 2010

Medical Image Computing and Computer-Assisted Intervention – MICCAI 2010

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“…Examples include the absence of tau mutations linked to AD except for a triple transgenic mouse 3xTg-AD, bearing mutations for APP, PSEN1/2, and TAU (9); inability to develop the whole spectrum of the disease; overexpression of transgenes into a nonphysiological scenario; and the fact that the manipulated genes represent only familial, not sporadic forms of AD (10,11). It would be highly desirable to have a nontransgenic model of AD to complement the existing models.…”

mentioning

confidence: 99%

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Ardiles

Tapia-Rojas

Mandal

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

122

107

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Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-β (Aβ) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aβ oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated. memory dysfunction | neural plasticity | aging | T-maze | hippocampus A lzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of abnormally processed proteins in neurofibrillary tangles (NFTs) and senile plaques (1). These lesions are present in both familial and sporadic forms of AD. Familial AD is linked to inherited mutations in AD-related genes and represents a small percentage of AD cases, whereas sporadic AD represents the vast majority of cases and is not inherited. Results from transgenic mice bearing mutations in APP, PSEN1/2, and TAU show synaptic dysfunction in early stages of AD, before overt neurodegeneration (2, 3). More recent studies have demonstrated a critical role for soluble Aβ oligomers as an early trigger for AD, as well as associations with memory and neural plasticity loss (4-8).Although transgenic mice have been extremely useful in elucidating the pathological mechanisms of AD, they have some substantial limitations. Examples include the absence of tau mutations linked to AD except for a triple transgenic mouse 3xTg-AD, bearing mutations for APP, PSEN1/2, and TAU (9); inability to develop the whole spectrum of the disease; overexpression of transgenes into a nonphysiological scenario; and the fact that the manipulated genes represent only familial, not sporadic forms of AD (10, 11). It would be highly desirable to have a nontransgenic model of AD to complement the existing models. Several species naturally develop features of AD with age; however, the usefulness of these species is limited, because none exhibits the full spectrum of AD-related alterations (12-14). For example, the Aβ peptide sequences of Cavia porcellus (guinea pig) and Microcebus murinus are similar to that of huma...

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“…This hypothesis may give an explanation of the common pathogenic mechanisms and inflammatory gene polymorphisms involved in both AD and type 2 diabetes. In both diseases amyloidosis, that is, the accumulation of insoluble aggregates of fibrillar proteins, occurs in various organs and is often associated with bacterial infections [174]. Thus, the accumulation of intraneuronal amyloid-β peptide (Aβ) appears to be an early event in AD, suggesting its important role in the neurodegenerative process of AD, because Aβ aggregates, particularly oligomers, may lead to synaptic dysfunction and neuronal loss, which are associated with memory and neural plasticity loss.…”

Section: Sporadic Models For Alzheimer's Studymentioning

confidence: 99%

Alzheimer's Disease: From Animal Models to the Human Syndrome

Orta‐Salazar¹,

Vargas‐Rodríguez²,

Castro-Chavira³

et al. 2016

Update on Dementia

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Some animal models, genetically modified (such as murine) and sporadic (as others species), enable the study of the origin of specific lesions observed in human neurodegenerative diseases. In particular, Alzheimer's disease (AD) models have been designed to test the hypothesis that certain lesions are associated with functional and morphological changes beginning with memory loss and impairment in activities of daily life. This review compares and evaluates the phenotypes of different AD animal models, on the basis of the specific objectives of each study, with the purpose of encompassing their contributions to the comprehension of the AD signs and symptoms in humans. All these models contribute to the comprehension of the human AD mechanisms regarding the heterogeneity of AD phenotypes: the overlap between AD and age-related changes, the variability of AD onset (early or late), the probable reactiveness of amyloid-β and tau proteins, the scarcity of senile plaques and/or neurofibrillary tangles in some AD cases, the spatial correlation of the pathology and cerebral blood vessels, and the immunological responses (microglial aging) and synaptopathy. Altogether, these considerations may contribute to find therapies to treat and prevent this disease.

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Transgenic mouse models of Alzheimer's disease: How useful have they been for therapeutic development?

Cited by 92 publications

References 83 publications

Characterizing the Regional Structural Difference of the Brain between Tau Transgenic (rTg4510) and Wild-Type Mice Using MRI

Characterizing the Regional Structural Difference of the Brain between Tau Transgenic (rTg4510) and Wild-Type Mice Using MRI

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Alzheimer's Disease: From Animal Models to the Human Syndrome

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