Background Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a
major pathological hallmark of Alzheimer’s disease (AD) brain. Of special interest is the effect of cerebral amyloid beta
deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral
amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on
their interplay.
Methods We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in
terms of correlation of gene expression data with human brain regions, development of Alzheimer’s-like pathology,
synaptic transmission, and behavior.
Results The main findings are an interaction of human beta-amyloid and human tau in crossbred 5xFADxhtau-KI
observed at transcriptional level and corroborated by electrophysiology and histopathology. The comparison of
gene expression data of the 5xFADxhtau-KI mouse model to 5xFAD, control mice and to human AD patients revealed
conspicuous changes in pathways related to mitochondria biology, extracellular matrix, and immune function.
These changes were accompanied by plaque-associated MC1-positive pathological tau that required the htau-KI
background. LTP deficits were noted in 5xFAD and htau-KI mice in contrast to signs of rescue in 5xFADxhtau-KI mice.
Increased frequencies of miniature EPSCs and miniature IPSCs indicated an upregulated presynaptic function in
5xFADxhtau-KI.
Conclusion In summary, the multiple interactions observed between knocked-in human tau and the 5xFAD-driven
progressing amyloidosis have important implications for future model development in AD.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:93546 |
| Date | 03 September 2024 |
| Creators | Barendrecht, Susan, Schreurs, An, Geissler, Stefanie, Sabanov, Victor, Ilse, Victoria, Rieckmann, Vera, Eichentopf, Rico, Künemund, Anja, Hietel, Benjamin, Wussow, Sebastian, Hoffmann, Katrin, Körber‑Ferl, Kerstin, Pandey, Ravi, Carter, Gregory W., Demuth, Hans‑Ulrich, Holzer, Max, Roßner, Steffen, Schilling, Stephan, Preuss, Christoph, Balschun, Detlef, Cynis, Holger |
| Publisher | BioMed Central |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 16, 10.1186/s13195-022-01144-y |
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