| First Author | Nies SH | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 4 | Pages | 101159 |
| PubMed ID | 34480901 | Mgi Jnum | J:310638 |
| Mgi Id | MGI:6764398 | Doi | 10.1016/j.jbc.2021.101159 |
| Citation | Nies SH, et al. (2021) Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-beta. J Biol Chem 297(4):101159 |
| abstractText | In Alzheimer's disease (AD), deposition of pathological tau and amyloid-beta (Abeta) drive synaptic loss and cognitive decline. The injection of misfolded tau aggregates extracted from human AD brains drives templated spreading of tau pathology within WT mouse brain. Here, we assessed the impact of Abeta copathology, of deleting loci known to modify AD risk (Ptk2b, Grn, and Tmem106b) and of pharmacological intervention with an Fyn kinase inhibitor on tau spreading after injection of AD tau extracts. The density and spreading of tau inclusions triggered by human tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1DeltaE9 transgenic and App(NL-F/NL-F) knock-in mice. In mice with human tau sequence replacing mouse tau, template matching enhanced neuritic tau burden. Human AD brain tau-enriched preparations contained aggregated Abeta, and the Abeta coinjection caused a redistribution of Abeta aggregates in mutant AD model mice. The injection-induced Abeta phenotype was spatially distinct from tau accumulation and could be ameliorated by depleting Abeta from tau extracts. These data suggest that Abeta and tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Abeta-oligomer-induced signaling, or deleting expression of the progranulin and TMEM106B lysosomal proteins, did not alter the somatic tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic tau after injection of human AD tau seeds into WT mice. These studies refine our knowledge of factors capable of modulating tau spreading. |
