A novel human tau knock-in mouse model reveals interaction of Abeta and human tau under progressing cerebral amyloidosis in 5xFAD mice. Alzheimers Res Ther. 2023;15(1):16.
JMG, Mice, Humans, Animals, Amyloid beta-Peptides, Mice, Transgenic, Alzheimer Disease, tau Proteins, Amyloidosis, Brain, Disease Models, Animal, Amyloid beta-Protein Precursor
Alzheimers Res Ther. 2023;15(1):16.
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Alzheimer’s Association (grant: 2016‐NIRG‐396‐583) and National Institutes of Health (grant: U54 AG054345). The work in Leuven was supported by a research grant from FWO Flanders to DB (G0D76.14) and a scholarship from the Agency for Innovation by Science and Technology in Flanders (IWT) to AS (141698).
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.