Transgenic amyloid models

Amyloid precursor protein (APP) and Alzheimer ’s disease

Cleavage of the amyloid precursor protein (APP) leads to generation of amyloid beta (Aβ) protein fragments. An early event in the pathology of Alzheimer’s disease (AD) is the oligomerization of Aβ and the formation of amyloid plaques. The formation of these protein oligomers and aggregates is due to an imbalance between the production of Aβ from the APP protein and clearance of Aβ. These aggregates are toxic in cell cultures and are thought to underlie downstream pathology, including synaptic toxicity, neurodegeneration and inflammation.

Transgenic APP and APP/PS1 modelsalzheimers-disease

Classical transgenic mouse models of Alzheimer’s disease express the human APP gene with mutations that cause early-onset familial AD. The earliest transgenic model, the Tg2576 model, expressed human APP with the Swedish mutations. This model develops classical amyloid plaque pathology from approximately 12 months onwards. More recently, APP/PS1 models were developed that expresses both mutations in the APP gene and in the Presenilin 1 gene. This yields a higher level of Aβ1-42, which is much more toxic and aggregation prone than Aβ1-40 and as a consequence these models shows amyloid plaques much earlier, from around 3 – 6 months of age depending on the model.

Cognitive deficits in amyloid models

Transgenic APP and APP/PS1 models show robust cognitive impairments, for instance in the Morris Water Maze. Recent studies by others and us show that cognitive impairments can already be detected before plaque onset. In particular, our sensitive CognitionWall™ Discrimination learning task detects learning impairments already at the age of 3 months in APP/PS1 mice, when deficits in the Morris Water Maze are not evident yet.

Biomarkers

The number and size of amyloid plaques can be quantified after immunohistochemical (IHC) staining of brain slices. For these analyses, we use the 6E10 antibody to detect amyoid plaques. Using IHC, changes in markers of neuroinflammation can be visualized by us. In addition, we measure Aβ levels in the brain, cerebrospinal fluid and blood using sensitive ELISA. For example, acute treatment with a BACE1 inhibitor, an enzyme critically involved in the generation of toxic Aβ species, effectively reduces the amount of Aβ42 in brain tissue a few hours after treatment.

Preclinical proof of concept studies at Sylics

The robustness of amyloid pathology and behavioral changes seen in APP models make them suitable models for drug discovery studies. Typical proof of concept studies at Sylics employ chronic administration of the therapeutic substance, longitudinal assessment of a protective effect on cognitive function and post-mortem analyses of biomarkers. Sylics employs transgenic Tg2576 and APP/PS1 models for fee-for-service studies. For further information on this model and possibilities, please contact us at info@sylics.com.