Abstract
Recent studies suggest that misfolded tau molecules can be released, and taken up by adjacent neurons, propagating proteopathic seeds across neural systems. Yet critical to understanding whether tau propagation is relevant in pathophysiology of disease would be to learn if it alters neuronal properties. We utilized high resolution multi-color in situ hybridization technology, RNAScope, in a well-established tau transgenic animal, and found that a subset of neurons in the cortex do not appear to express the transgene, but do develop phospho-tau positive inclusions, consistent with having received tau seeds. Recipient neurons show decreases in their expression of synaptophysin, CAMKIIα, and mouse tau in both young and old animals. These results contrast with neurons that develop tau aggregates and also overexpress the transgene, which have few changes in expression of metabolic and synaptic markers. Taken together, these results strongly suggest that tau propagation impacts neuronal functional integrity.
Highlights
Accumulating evidence suggest that hyperphosphorylated or misfolded conformers of the microtubule associated protein Tau, which accumulates as aggregates in several neurodegenerative diseases including Alzheimer’s disease (AD) and some forms of frontotemporal dementia, have the ability to “spread” through the brain [4, 5, 7, 12, 20, 23]
In this study, we examined the effect of human P301L transgene on gene expression in individual neurons in the responsive element strain FVB-Tg(tetO-MAPT*P301L)4510/Kha/Jlws (rTg4510) mouse model of tauopathy, focusing on changes that had previously been shown to occur in human AD in synaptic and metabolic pathways [9]
We were able to distinguish the effects of transgene overexpression and tau aggregation
Summary
Accumulating evidence suggest that hyperphosphorylated or misfolded conformers of the microtubule associated protein Tau, which accumulates as aggregates in several neurodegenerative diseases including Alzheimer’s disease (AD) and some forms of frontotemporal dementia, have the ability to “spread” through the brain [4, 5, 7, 12, 20, 23]. It has been suggested that tau can form proteopathic seeds that contaminate neurons through a trans-synaptic mechanism in a prion-like manner [22, 31]. Consistent with this idea, tau was shown to actively spread from neuron to neuron in various model. We examined two independent cohorts of mice, one younger and one older, to assess reproducibility and assess potential age effects This allowed us to address the question of whether the presence of the transgene (and soluble tau), and/or aggregated tau, impacts the phenotypes of synaptic and metabolic dysfunction in neurons that are the recipients of proteopathic seeds
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