A transgenic rat model of Alzheimer's disease with extracellular Aβ deposition (original) (raw)
Abeta deposition and related pathology in an APP x PS1 transgenic mouse model of Alzheimer's disease
PubMed, 2008
A transgenic mouse bearing mutant transgenes linked to familial forms of Alzheimer's disease (AD) for the amyloid precursor protein and presenilin-1 (TASTPM) showed Abeta plaque deposition and age-related histological changes in associated brain pathology. The Abeta present was of multiple forms, including species with a C-terminus at position 40 or 42, as well as an N-terminus at position 1 or truncated in a pyro-3-glutamate form. Endogenous rodent Abeta was also present in the deposits. Laser capture microdissection extracts showed that multimeric forms of Abeta were present in both plaque and tissue surrounding plaques. Associated with the Abeta deposits was evidence of an inflammatory response characterised by the presence of astrocytes. Also present in close association with the deposits was phosphorylated tau and cathepsin D immunolabelling. The incidence of astrocytes and of phosphorylated tau and cathepsin D load showed that both of these potential disease markers increased in parallel to the age of the mice and with Abeta deposition. Immunohistochemical labelling of neurons in the cortex and hippocampus of TASTPM mice suggested that the areas of Abeta deposition were associated with the loss of neurons. TASTPM mice, therefore, exhibit a number of the pathological characteristics of disease progression in AD and may provide a means for assessment of novel therapeutic agents directed towards modifying or halting disease progression.
Neuroscience, 2003
Alzheimer's disease (AD) is the most common form of dementia in the elderly, and the characteristic pathological hallmarks of the disease are neuritic plaques and neurofibrillary tangles. The sequence of events leading to the extracellular deposition of amyloidbeta (Abeta) peptides in plaques or in diffuse deposits is not clear. Here we investigate the relation between disrupted axonal transport of amyloid precursor protein (APP) and/or Abeta and the deposition of Abeta in the deafferented terminal fields in APP/presenilin 1 double-transgenic AD-model mice. In the first experiment we ablated entorhinal cortex neurons and examined the subsequent changes in amyloid deposition in the hippocampus 1 month later. We show that there is a substantial reduction in the amount of diffuse amyloid deposits in the denervated areas of the hippocampus. Further, to investigate the effects of long-term deafferentation, in a second experiment we cut the fimbria-fornix and analyzed the brains 11 mo...
Deposition of mouse amyloid β in human APP/PS1 double and single AD model transgenic mice
Neurobiology of Disease, 2006
The deposition of amyloid β (Aβ) peptides and neurofibrillary tangles are the two characteristic pathological features of Alzheimer's disease (AD). To investigate the relation between amyloid precursor protein (APP) production, amyloid β deposition and the type of Aβ in deposits, i.e., human and/or mouse, we performed a histopathological analysis, using mouse and human specific antibodies, of the neocortex and hippocampus in 6, 12 and 19 months old APP/PS1 double and APP and PS1 single transgenic mice. There was a significant correlation between the human amyloid β deposits and the intrinsic rodent amyloid β deposits, that is, all plaques contained both human and mouse Aβ, and the diffuse amyloid β deposits also colocalized human and mouse Aβ. Furthermore, some blood vessels (mainly leptomeningeal vessels) show labeling with human Aβ, and most of these vessels also label with mouse Aβ. Our findings demonstrate that the human amyloid deposits in APP/PS1 transgenic mice are closely associated with mouse Aβ, however, they do not precisely overlap. For instance, the core of plaques consists of primarily human Aβ, whereas the rim of the plaque contains both human and mouse amyloid β, similarly, human and mouse Aβ are differentially localized in the blood vessel wall. Finally, as early as amyloid β deposits can be detected, they show the presence of both human and mouse Aβ. Together, these data indicate that mouse Aβ is formed and deposited in significant amounts in the AD mouse brain and that it is deposited together with the human Aβ.
Journal of Alzheimer's disease: JAD
Alzheimer's disease (AD) is a neurodegenerative pathology in which amyloid-beta (Abeta) peptide accumulates in different brain areas leading to deposition of plaques and a progressive decline of cognitive functions. After a decade in which a number of transgenic (Tg) mouse models mimicking AD-like amyloid-deposition pathology have been successfully generated, few rat models have been reported that develop intracellular and extracellular Abeta accumulation, together with impairment of cognition. The generation of a Tg rat reproducing the full AD-like amyloid pathology has been elusive. Here we describe the generation and characterization of a new transgenic rat line, coded McGill-R-Thy1-APP, developed to express the human amyloid-beta precursor protein (AbetaPP) carrying both the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter. The selected mono-transgenic line displays an extended phase of intraneuronal Abeta accumulation, already apparent at 1 week...
Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology
Proceedings of the National Academy of Sciences, 1997
Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid  (A) peptide, the major constituent of AD plaques. We expressed human APP 751 containing these mutations in the brains of transgenic mice. Two transgenic mouse lines develop pathological features reminiscent of AD. The degree of pathology depends on expression levels and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670͞671 combined with the V717I mutation causes A deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits are mostly of the diffuse type; however, some congophilic plaques can be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are Congo Red-positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inf lammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. The immunoreactivity is exclusively found in congophilic senile plaques of both lines. In the higher expressing line, elevated tau phosphorylation can be demonstrated biochemically in 6-month-old animals and increases with age. These mice resemble major features of AD pathology and suggest a central role of A in the pathogenesis of the disease.
Endogenous murine Aβ increases amyloid deposition in APP23 but not in APPPS1 transgenic mice
Neurobiology of Aging, 2015
Wegenast-Braun, B.M., Endogenous murine Aβ increases amyloid deposition in APP23 but not in APPPS1 transgenic mice, Neurobiology of Aging (2015), Brion JP (2010) Deletion of murine tau gene increases tau aggregation in a human mutant tau transgenic mouse model. Biochem Soc Trans 38:1001-1005. Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, Abramowski D, Sturchler-Pierrat C, Sommer B, Staufenbiel M, Jucker M (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci U S A 96:14088-14093. Calhoun ME, Wiederhold KH, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, Staufenbiel M, Sommer B, Jucker M (1998) Neuron loss in APP transgenic mice. Nature 395:755-756. Duyckaerts C, Potier MC, Delatour B (2008) Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol 115:5-38. 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Morales-Corraliza J, Mazzella MJ, Berger JD, Diaz NS, Choi JH, Levy E, Matsuoka Y, Planel E, Mathews PM (2009) In vivo turnover of tau and APP metabolites in the brains of wild-type and Tg2576 mice: greater stability of sAPP in the beta-amyloid depositing mice. PLoS One 4:e7134. Morales-Corraliza J, Schmidt SD, Mazzella MJ, Berger JD, Wilson DA, Wesson DW, Jucker M, Levy E, Nixon RA, Mathews PM (2013) Immunization targeting a minor plaque constituent clears betaamyloid and rescues behavioral deficits in an Alzheimer's disease mouse model. Neurobiology of aging 34:137-145. Pype S, Moechars D, Dillen L, Mercken M (2003) Characterization of amyloid beta peptides from brain extracts of transgenic mice overexpressing the London mutant of human amyloid precursor protein. J Neurochem 84:602-609. 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Experimental Gerontology, 2000
In transgenic mice that overexpress mutant Amyloid Precursor Protein [V717I], or APP/London (APP/Lo) (1999a. Early phenotypic changes in transgenic mice that overexpress different mutants of Amyloid Precursor Protein in brain. J. Biol. Chem. 274, 6483±6492; 1999b. Premature death in transgenic mice that overexpress mutant Amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. Neuroscience 91, 819±830) the AD related phenotype of plaque and vascular amyloid pathology is late (12±15 months). This typical and diagnostic pathology is thereby dissociated in time from early symptoms (3±9 months) that include disturbed behavior, neophobia, aggression, glutamate excitotoxicity, defective cognition and decreased LTP. The APP/Lo transgenic mice are therefore a very interesting model to study early as well as late pathology, including the effect of age. In ageing APP*Lo mice, brain soluble and especially ªinsolubleº amyloid peptides dramatically increased, while normalized levels of secreted APPsa and APPsb, as well as cell-bound b-C-stubs, remained remarkably constant, indicating normal a-and b-secretase processing of APP. In double transgenic mice, i.e. APP=Lo £ PS1; clinical mutant PS1[A246E] but not wild-type human PS1 increased Ab, and plaques and vascular amyloid developed at age 6±9 months. The PS1 mutant caused increasing Ab42 production, while ageing did not. Amyloid deposits are thus formed, not by overproduction of Ab, but by lack of clearance and/or degradation in the brain of ageing APP/Lo transgenic mice. The clearance pathways of the cerebral amyloid peptides are therefore valuable targets for fundamental research and for therapeutic potential. Although hyper-phosphorylated protein tau was evident in swollen neurites around the amyloid plaques, neuro®brillary pathology is not observed and the ªtangleº aspect of AD pathology is therefore still missing from all current transgenic ªamyloidº models. Also the ªApoE4º risk for late onset AD remains a problem for I. Dewachter et al. / Experimental Gerontology 35 (2000) 831±841 831 Experimental Gerontology 35 (2000) 831±841 www.elsevier.nl/locate/expgero 0531-5565/00/$ -see front matter q modeling in transgenic mice. We have generated transgenic mice that overexpress human ApoE4 (2000. Expression of Human Apolipoprotein E4 in neurons causes hyperphosphorylation of Protein tau in the brains of transgenic mice. Am. J. Pathol. 156 (3) 951±964) or human protein tau (1999. Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am. J. Pathol. 155, 2153±2165) in their neurons. Both develop a similar although not identical axonopathy, with progressive degeneration of nerves and with muscle wasting resulting in motoric problems. Remarkably, ApoE4 transgenic mice are, like the tau transgenic mice, characterized by progressive hyper-phosphorylation of protein tau also in motor neurons which explains the motoric defects. Further crossing with the APP/Lo transgenic mice is ongoing to yield ªmultipleº transgenic mouse strains to study new aspects of amyloid and tau pathology. q 2000 Elsevier Science Inc. All rights reserved.
Neuron, 1997
Missense mutations in two related genes, termed presenilin 1 (PS1) and presenilin 2 (PS2), cause dementia in a subset of early-onset familial Alzheimer's disease (FAD) pedigrees. In a variety of experimental in vitro and in vivo settings, FAD-linked presenilin variants influence the processing of the amyloid precursor protein (APP), leading to elevated levels of the highly fibrillogenic Aβ1–42 peptides that are preferentially deposited in the brains of Alzheimer Disease (AD) patients. In this report, we demonstrate that transgenic animals that coexpress an FAD-linked human PS1 variant (A246E) and a chimeric mouse/human APP harboring mutations linked to Swedish FAD kindreds (APP swe) develop numerous amyloid deposits much earlier than age-matched mice expressing APP swe and wild-type Hu PS1 or APP swe alone. These results provide evidence for the view that one pathogenic mechanism by which FAD-linked mutant PS1 causes AD is to accelerate the rate of β-amyloid deposition in brain.
A transgenic rat expressing human APP with the Swedish Alzheimer’s disease mutation
Biochemical and Biophysical Research Communications, 2007
In recent years, transgenic mice have become valuable tools for studying mechanisms of Alzheimer's disease (AD). With the aim of developing an animal model better for memory and neurobehavioural testing, we have generated a transgenic rat model of AD. These animals express human amyloid precursor protein (APP) containing the Swedish AD mutation. The highest level of expression in the brain is found in the cortex, hippocampus, and cerebellum. Starting after the age of 15 months, the rats show increased tau phosphorylation and extracellular Ab staining. The Ab is found predominantly in cerebrovascular blood vessels with very rare diffuse plaques. We believe that crossing these animals with mutant PS1 transgenic rats will result in accelerated plaque formation similar to that seen in transgenic mice.