Synaptic and metabolic gene expression alterations in neurons that are recipients of proteopathic tau seeds
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020) 8:168
Open Access
RESEARCH
Synaptic and metabolic gene expression alterations in neurons that are recipients of proteopathic tau seeds Marta Perez‑Rando1,2, Simon Dujardin1,2 , Rachel E. Bennett1,2, Caitlin Commins1, Tara Nibhanupudy1 and Bradley T. Hyman1,2*
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 patho‑ physiology 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. Keywords: Alzheimer’s disease, Neurofibrillary tangles, Tau seeding, RNA expression
Introduction 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 now 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 *Correspondence: [email protected] 1 Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Building 114, Room 2009, Charlestown, MA 02129, USA Full list of author information is available at the end of the article
systems. For example, in a transgenic model where tau is exclusively expressed in the entorhinal cortex, tau spreads to limbic and neocortical structures [7, 21]. In addition, after focal injections of viral vectors, human tau spreads from the viruses injection site to different connected areas [15, 32]. Additionally, direct injections of human tau aggregates into the brain of mice can lead to aggregate formation in neurons [3, 11, 19]. In these models, neurons that receive projections from tau expressing neurons develop tau aggregates suggesting the existence of a mechanism of proteopathic seeding happening in tau propagation “recipient” neurons [25]. However, despite detailed studies of the mechanisms of tau propagation, it is unknown how tau uptake impacts the biology of the recipient neurons. Alterations in gene e
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