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 WT mouse brain. Here, we assessed the impact of Aβ 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/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 Aβ, and the Aβ coinjection 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–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.
Highlights
In Alzheimer’s disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline
There were no significant changes in tau high–molecular-weight aggregates or phosphorylation when comparing samples from extracts stored at 4 C every 12 h (Fig. 1C)
To test the potency of our tau extracts in vitro, we treated days in vitro (DIV) 7 primary WT mouse neurons with 0.25% (v/v) tau extracts for 14 days and measured tau pathology within the area occupied by neurons (Fig. 1E)
Summary
In Alzheimer’s disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline. Mouse aging had a prominent effect to increase the accumulation of neuritic tau after injection of human AD tau seeds into WT mice. Tau from different AD subjects generated somatic and neuritic inclusions in WT mice To ascertain if our tau extracts showed seeding activity in vivo, we injected WT animals as described previously [18].
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