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Modeling Alzheimer's disease in transgenic rats.

Do Carmo S, Cuello AC - Mol Neurodegener (2013)

Bottom Line: Rats are physiologically, genetically and morphologically closer to humans.More importantly, the rat has a well-characterized, rich behavioral display.Consequently, rat models of AD should allow a more sophisticated and accurate assessment of the impact of pathology and novel therapeutics on cognitive outcomes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Room 1325, Montreal, Quebec H3G 1Y6, Canada. claudio.cuello@mcgill.ca.

ABSTRACT
Alzheimer's disease (AD) is the most common form of dementia. At the diagnostic stage, the AD brain is characterized by the accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss. Despite the large variety of therapeutic approaches, this condition remains incurable, since at the time of clinical diagnosis, the brain has already suffered irreversible and extensive damage. In recent years, it has become evident that AD starts decades prior to its clinical presentation. In this regard, transgenic animal models can shed much light on the mechanisms underlying this "pre-clinical" stage, enabling the identification and validation of new therapeutic targets. This paper summarizes the formidable efforts to create models mimicking the various aspects of AD pathology in the rat. Transgenic rat models offer distinctive advantages over mice. Rats are physiologically, genetically and morphologically closer to humans. More importantly, the rat has a well-characterized, rich behavioral display. Consequently, rat models of AD should allow a more sophisticated and accurate assessment of the impact of pathology and novel therapeutics on cognitive outcomes.

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The McGill-R-Thy1-APP transgenic rat phenotype. (A) The McGill-R-Thy1-APP transgenic rat expresses the human APP751, bearing the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter. Its phenotype is fairly similar to the human pathology reported in AD and MCI. (B) We observe intraneuronal Aβ accumulation starting at 1 week post-natal, as determined with our murine monoclonal antibody (McSA1) against the N-terminus of the Aβ peptide. The development of plaques follows the same anatomical sequence as in humans. Mature amyloid plaques are Thioflavin S-positive (C) and are surrounded by activated microglia as observed with MHCII- (brown) and Aβ-specific antibodies (McSA1-blue) and also with Iba-1(blue) and McSA1(blue) (D). Plaques are also accompanied by dystrophic neurites (E) and astrogliosis (GFAP-blue, McSA1-green) (F). (G) These rats already show learning deficits in the Morris water maze task at the pre-plaque stage (3 months old) and these deficits progress with amyloid accumulation. Images adapted from[81] with the publisher’s permission and from[83].
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Figure 1: The McGill-R-Thy1-APP transgenic rat phenotype. (A) The McGill-R-Thy1-APP transgenic rat expresses the human APP751, bearing the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter. Its phenotype is fairly similar to the human pathology reported in AD and MCI. (B) We observe intraneuronal Aβ accumulation starting at 1 week post-natal, as determined with our murine monoclonal antibody (McSA1) against the N-terminus of the Aβ peptide. The development of plaques follows the same anatomical sequence as in humans. Mature amyloid plaques are Thioflavin S-positive (C) and are surrounded by activated microglia as observed with MHCII- (brown) and Aβ-specific antibodies (McSA1-blue) and also with Iba-1(blue) and McSA1(blue) (D). Plaques are also accompanied by dystrophic neurites (E) and astrogliosis (GFAP-blue, McSA1-green) (F). (G) These rats already show learning deficits in the Morris water maze task at the pre-plaque stage (3 months old) and these deficits progress with amyloid accumulation. Images adapted from[81] with the publisher’s permission and from[83].

Mentions: The McGill-R-Thy1-APP rat model is the only model able to reproduce extensive AD-like amyloid pathology with a single transgene (Figure 1)[81]. This model expresses the hAPP751, bearing the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter. In the McGill-R-Thy1-APP transgenic rat, a single transgene is able to produce human APP expression specifically in AD-relevant areas of the brain without cerebellar and peripheral tissue expression. The presence of a single transgene with a low copy number makes of this rat the least genetically aggressive AD transgenic model developed so far.


Modeling Alzheimer's disease in transgenic rats.

Do Carmo S, Cuello AC - Mol Neurodegener (2013)

The McGill-R-Thy1-APP transgenic rat phenotype. (A) The McGill-R-Thy1-APP transgenic rat expresses the human APP751, bearing the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter. Its phenotype is fairly similar to the human pathology reported in AD and MCI. (B) We observe intraneuronal Aβ accumulation starting at 1 week post-natal, as determined with our murine monoclonal antibody (McSA1) against the N-terminus of the Aβ peptide. The development of plaques follows the same anatomical sequence as in humans. Mature amyloid plaques are Thioflavin S-positive (C) and are surrounded by activated microglia as observed with MHCII- (brown) and Aβ-specific antibodies (McSA1-blue) and also with Iba-1(blue) and McSA1(blue) (D). Plaques are also accompanied by dystrophic neurites (E) and astrogliosis (GFAP-blue, McSA1-green) (F). (G) These rats already show learning deficits in the Morris water maze task at the pre-plaque stage (3 months old) and these deficits progress with amyloid accumulation. Images adapted from[81] with the publisher’s permission and from[83].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231465&req=5

Figure 1: The McGill-R-Thy1-APP transgenic rat phenotype. (A) The McGill-R-Thy1-APP transgenic rat expresses the human APP751, bearing the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter. Its phenotype is fairly similar to the human pathology reported in AD and MCI. (B) We observe intraneuronal Aβ accumulation starting at 1 week post-natal, as determined with our murine monoclonal antibody (McSA1) against the N-terminus of the Aβ peptide. The development of plaques follows the same anatomical sequence as in humans. Mature amyloid plaques are Thioflavin S-positive (C) and are surrounded by activated microglia as observed with MHCII- (brown) and Aβ-specific antibodies (McSA1-blue) and also with Iba-1(blue) and McSA1(blue) (D). Plaques are also accompanied by dystrophic neurites (E) and astrogliosis (GFAP-blue, McSA1-green) (F). (G) These rats already show learning deficits in the Morris water maze task at the pre-plaque stage (3 months old) and these deficits progress with amyloid accumulation. Images adapted from[81] with the publisher’s permission and from[83].
Mentions: The McGill-R-Thy1-APP rat model is the only model able to reproduce extensive AD-like amyloid pathology with a single transgene (Figure 1)[81]. This model expresses the hAPP751, bearing the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter. In the McGill-R-Thy1-APP transgenic rat, a single transgene is able to produce human APP expression specifically in AD-relevant areas of the brain without cerebellar and peripheral tissue expression. The presence of a single transgene with a low copy number makes of this rat the least genetically aggressive AD transgenic model developed so far.

Bottom Line: Rats are physiologically, genetically and morphologically closer to humans.More importantly, the rat has a well-characterized, rich behavioral display.Consequently, rat models of AD should allow a more sophisticated and accurate assessment of the impact of pathology and novel therapeutics on cognitive outcomes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Room 1325, Montreal, Quebec H3G 1Y6, Canada. claudio.cuello@mcgill.ca.

ABSTRACT
Alzheimer's disease (AD) is the most common form of dementia. At the diagnostic stage, the AD brain is characterized by the accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss. Despite the large variety of therapeutic approaches, this condition remains incurable, since at the time of clinical diagnosis, the brain has already suffered irreversible and extensive damage. In recent years, it has become evident that AD starts decades prior to its clinical presentation. In this regard, transgenic animal models can shed much light on the mechanisms underlying this "pre-clinical" stage, enabling the identification and validation of new therapeutic targets. This paper summarizes the formidable efforts to create models mimicking the various aspects of AD pathology in the rat. Transgenic rat models offer distinctive advantages over mice. Rats are physiologically, genetically and morphologically closer to humans. More importantly, the rat has a well-characterized, rich behavioral display. Consequently, rat models of AD should allow a more sophisticated and accurate assessment of the impact of pathology and novel therapeutics on cognitive outcomes.

Show MeSH
Related in: MedlinePlus