RRC ID 68007
Author Nies SH, Takahashi H, Herber CS, Huttner A, Chase A, Strittmatter SM.
Title Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β.
Journal J Biol Chem
Abstract In Alzheimer's Disease (AD), deposition of pathological Tau and Amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded Tau aggregates extracted from human AD brains drives templated spreading of Tau pathology within wild type mouse brain. Here, we assessed the impact of Aß co-pathology, of deleting loci known to modify AD risk (Ptk2b, Grn, Tmem106b) and of pharmacological intervention with a 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/PSEN1ΔE9 transgenic and AppNL-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 Aß, and the Aß co-injection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from Tau accumulation and could be ameliorated by depleting Aβ from Tau extracts. These data suggest that Aβ and Tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer (Aβo) induced signaling, or deleting expression of the PGRN 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 wild type mice. These studies refine our knowledge of factors capable of modulating Tau spreading.
Volume 297(4)
Pages 101159
Published 2021-10-1
DOI 10.1016/j.jbc.2021.101159
PII S0021-9258(21)00961-3
PMID 34480901
PMC PMC8477193
MeSH Aging / genetics Aging / metabolism* Alzheimer Disease / genetics Alzheimer Disease / metabolism* Amyloid beta-Peptides / genetics Amyloid beta-Peptides / metabolism* Animals Cerebral Cortex / metabolism* Hippocampus / metabolism* Mice Mice, Knockout Neurites / metabolism* tau Proteins / genetics tau Proteins / metabolism*
IF 4.238
Mice RBRC02370