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000266329 1001_ $$0P:(DE-2719)2811766$$aFerreira Rodrigues, Sara$$b0$$eFirst author
000266329 245__ $$aSpreading of Tau Protein Does Not Depend on Aggregation Propensity.
000266329 260__ $$aNew York, NY$$bSpringer$$c2023
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000266329 520__ $$aThe stereotypical progression of Tau pathology during Alzheimer disease has been attributed to trans-neuronal spreading of misfolded Tau proteins, followed by prion-like templated aggregation of Tau. The nature of Tau and the cellular mechanisms of Tau spreading are still under debate. We hypothesized that Tau's propensity for aggregation would correlate with its ability to spread across synapses and propagate pathology. To study the progressive propagation of Tau proteins in brain regions relevant for Alzheimer disease, we used mice expressing near-physiological levels of full-length human Tau protein carrying pro-aggregant (TauΔK280, TauΔK) or anti-aggregant (TauΔK280-PP, TauΔK-PP) mutations in the entorhinal cortex (EC). To enhance Tau expression in the EC, we performed EC injections of adeno-associated virus (AAV) particles encoding TauΔK or TauΔK-PP. The brains of injected and non-injected EC/TauΔK and EC/TauΔK-PP mice were studied by immunohistological and biochemical techniques to detect Tau propagation to dentate gyrus (DG) neurons and Tau-induced pathological changes. Pro- and anti-aggregant mice had comparable low transgene expression (~0.2 times endogenous mouse Tau). They accumulated human Tau at similar rates and only in expressing EC neurons, including their axonal projections of the perforant path and presynaptic terminals in the molecular layer of the DG. Pro-aggregant EC/TauΔK mice showed misfolded Tau and synaptic protein alterations in EC neurons, not observed in anti-aggregant EC/TauΔK-PP mice. Additional AAV-mediated expression of TauΔK or TauΔK-PP in EC/TauΔK or EC/TauΔK-PP mice, respectively, increased the human Tau expression to ~0.65 times endogenous mouse Tau, with comparable spreading of TauΔK and TauΔK-PP throughout the EC. There was a low level of transcellular propagation of Tau protein, without pathological phosphorylation or misfolding, as judged by diagnostic antibodies. Additionally, TauΔK but not TauΔK-PP expression induced hippocampal astrogliosis. Low levels of pro- or anti-aggregant full-length Tau show equivalent distributions in EC neurons, independent of their aggregation propensity. Increasing the expression via AAV induce local Tau misfolding in the EC neurons, synaptotoxicity, and astrogliosis and lead to a low level of detectable trans-neuronal spreading of Tau. This depends on its concentration in the EC, but, contrary to expectations, does not depend on Tau's aggregation propensity/misfolding and does not lead to templated misfolding in recipient neurons.
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000266329 650_7 $$2Other$$aAggregation propensity
000266329 650_7 $$2Other$$aAlzheimer disease
000266329 650_7 $$2Other$$aNeuroinflammation
000266329 650_7 $$2Other$$aTau pathology
000266329 650_7 $$2Other$$aTau spreading
000266329 650_7 $$2NLM Chemicals$$atau Proteins
000266329 650_2 $$2MeSH$$aMice
000266329 650_2 $$2MeSH$$aAnimals
000266329 650_2 $$2MeSH$$aHumans
000266329 650_2 $$2MeSH$$atau Proteins: genetics
000266329 650_2 $$2MeSH$$atau Proteins: metabolism
000266329 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000266329 650_2 $$2MeSH$$aTauopathies: metabolism
000266329 650_2 $$2MeSH$$aGliosis
000266329 650_2 $$2MeSH$$aHippocampus: metabolism
000266329 650_2 $$2MeSH$$aDisease Models, Animal
000266329 650_2 $$2MeSH$$aMice, Transgenic
000266329 7001_ $$0P:(DE-2719)9000008$$aAnglada-Huguet, Marta$$b1$$udzne
000266329 7001_ $$0P:(DE-2719)2810340$$aHochgräfe, Katja$$b2
000266329 7001_ $$0P:(DE-2719)2812350$$aKaniyappan, Senthilvelrajan$$b3$$udzne
000266329 7001_ $$0P:(DE-2719)2812695$$aWegmann, Susanne$$b4
000266329 7001_ $$0P:(DE-2719)2541658$$aMandelkow, Eva Maria$$b5$$eLast author
000266329 773__ $$0PERI:(DE-600)2071508-0$$a10.1007/s12031-023-02143-w$$gVol. 73, no. 9-10, p. 693 - 712$$n9-10$$p693 - 712$$tJournal of molecular neuroscience$$v73$$x0895-8696$$y2023
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