Exacerbation of tau pathology by pre‐existing amyloidosis in novel transgenic mice: Dysregulation of protein synthesis in neurodegeneration. (7th December 2020)

• Record Type: Journal Article
• Authors: Lewis, Jada; Xu, Guilian; Ulm, Brittany; Howard, John; Fromholt, Susan; Borchelt, David R.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.042291
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Numerous mouse models have been created to recapitulation of AD pathology; however, mouse models featuring Aβ‐related transgenes and mutations has been imperfect, resulting in Aβ plaques, synaptic and other AD‐related changes, but failing to fully recapitulate the downstream tau pathology. Conversely, mouse models with mutant tau demonstrate neurofibrillary tangle formation and neurodegeneration, while failing to demonstrate amyloid β pathology. While we and others have created model systems in which APP and tau pathologies were driven by concurrent expression of amyloid and tau transgenes or through the use of proteinaceous seeds, those systems failed to test the age‐associated, sequential nature of amyloidosis, and tauopathy as is suggested by the amyloid cascade hypothesis. In the current study, we have introduced late stage tau expression onto a background of pre‐existing amyloidosis to determine if this accelerated the development secondary tauopathy. Method: We crossed APPswe/PS1dE9 amyloidosis mice with rTg4510 conditional tauopathy mice to determine if inducing mutant human tau expression in aged brains of APPswe/PS1dE9/rTg4510 mice with pre‐existing amyloidosis accelerates "secondary" tauopathy. Mice were raised on doxycycline (to suppress transgenic tau expression) until ∼14 months of age, at which time transgenic tau expression was induced through the withdrawal of doxycycline in the diet. We evaluated the aggregation of phosphorylated tau and the activation of glia through immunohistochemistry. Result: We found that inducing mutant tau expression at 14‐15 months of age, in a background of substantial amyloid deposition, produced robust tau pathology by 20‐21 months of age as compared to rTg4510 transgenic mice lacking the amyloid pathology. In the triple transgenic model, neurofibrillary tangle pathology was evident throughout the cortex and hippocampus. Unexpectedly, the level of glial activation between triple transgenic and APPswe/PS1dE9 mice was similar with no obvious increase by the combination of amyloid and tau pathology. Conclusion: These data demonstrate that pre‐existing amyloidosis can exacerbate tauopathy and highlights the utility of delayed tau expression in modeling the amyloid cascade hypothesis.