Transgenic amyloid models
These models capitalize on the toxicity of amyloid in the brain to induce Alzheimer’s related pathology.
Sylics offers services with several different transgenic amyloid models. The choice of the best model depends on many factors, but all models present with amyloid plaques, inflammation, and cognitive deficits.
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Transgenic amyloid models that Sylics offers:
Amyloid oligomers and plaques
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. Most AD patients also have amyloid deposition on the blood vessels, termed cerebral amyloid angiopathy (CAA).
Mouse models of amyloid pathology
Mouse models of amyloid pathology (over)express human APP with familial AD-related mutations. These mouse models recapitulate the Aβ aggregation cascade, by expressing higher levels of the toxic Aβ1-40 and Aβ1-42 peptides. This leads to the deposition of plaques in the brain, CAA on the blood vessels, neuroinflammation, and many of the downstream consequences found in AD.
Sylics offers classic transgenic APP and APP/PS1 models. In addition, we offer services with APP targeted replacement (knock-in) humanized mice.
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 not only detects learning impairments at 6 months (Remmelink et al 2016), but already at the age of 3 months in APP/PS1 mice, when deficits in the Morris Water Maze are not evident yet.
The number and size of amyloid plaques and associated neuroinflammation can be quantified after immunohistochemical (IHC) staining of brain slices. In addition, we measure Aβ levels in the brain, cerebrospinal fluid, and blood using ultra-sensitive immunoassays.
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.
Drug screening studies in amyloid models
The biological and behavioral phenotypes make transgenic amyloid mice a valuable model of Alzheimer’s disease and suitable for drug-screening studies (Boeddrich et al, 2019). We have previously detected reduction of cognitive deficits after administration of BACE1 inhibitor LY2886721 in our sensitive Cognition Wall behavioral test.
Boeddrich A, Babila JT, Wiglenda T, Diez L, Jacob M, Nietfeld W, Huska MR, Haenig C, Groenke N, Buntru A, Blanc E, Meier JC, Vannoni E, Erck C, Friedrich B, Martens H, Neuendorf N, Schnoegl S, Wolfer DP, Loos M, Beule D, Andrade-Navarro MA, Wanker EE. The Anti-amyloid Compound DO1 Decreases Plaque Pathology and Neuroinflammation-Related Expression Changes in 5xFAD Transgenic Mice. Cell Chem Biol. 2019 Jan 17;26(1):109-120.e7. doi: 10.1016/j.chembiol.2018.10.013. Epub 2018 Nov 21. PMID: 30472115. https://pubmed.ncbi.nlm.nih.gov/30472115/
Keywords: Alzheimer’s disease, amyloid beta, Aβ, Abeta, neuroinflammation
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