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Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, Sanders DW, Cook C, Fu H, Boonen RA, Herman M, Nahmani E, Emrani S, Figueroa YH, Diamond MI, Clelland CL, Wray S, Duff KE. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016 Aug;19(8):1085-92. Epub 2016 Jun 20 PubMed.
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VU University Medical Center
Using elegant optogenetic and chemogenetic approaches, the authors show that pathological strains of tau are transferred cell-to-cell via the extracellular space, and that this propagation can be observed in “recipient” neurons that are more than one degree of connection removed from “donor” neurons that are seeded with a fibrillar tau strain. They also show that increased neuronal activity in hippocampus is associated with higher levels of extracellular tau, more rapid spread of tau to recipient neurons, and more rapid hippocampal atrophy in tau transgenic mice.
The notion that pathogenic proteins in various neurodegenerative conditions do not spread in a random fashion, but rather follow a prototypical pattern that spatially overlaps with disease-specific functional networks, has given rise to a “network model of neurodegeneration.” This evidence-based theory offers several mechanisms that may explain this orchestrated spread of disease, including “shared vulnerability” (i.e., neural populations with similar genetic and/or molecular properties may be equally susceptible), “trophic failure” (i.e., disruptions along functional pathways hinder transport of trophic sources), and “transneuronal spread” (i.e., proteins propagate along network connections). The latter has been investigated extensively lately, and seeding studies have shown that functional networks may indeed serve as a template to predict the spatial trajectory of toxic agents. These fundamental studies have been translated into human neuroimaging experiments (using functional MRI [fMRI] and diffusion tensor imaging [DTI]), which consistently showed that the functional architecture of the healthy brain dictates where pathology will spread, starting from a disease-specific epicenter.
Both basic science and human neuroimaging studies have thus provided evidence for the trans-synaptic spread hypothesis. It is still under debate, however, whether this cell-to-cell transmission occurs through actual physical connections or via the extracellular space. This study is important as it provides evidence for the latter — perhaps least intuitive — mechanism, and additionally showed that increased neural activity might facilitate the release and propagation of tau. Both findings have potential ramifications for disease-modifying therapies aiming to prevent spreading of the disease, as one might speculate that 1) it would be more feasible to target tau species in extracellular space compared to when it is embedded intracellularly, and 2) anti-epileptic drugs (e.g., levetiracetam) could prevent or slow the propagation of tau by reducing (hyper)activity of hippocampal neurons.
While reading this paper, it became clear to me that there is much room for improvement in terms of communication between researchers who are investigating the mechanistic properties of neurodegenerative diseases from a cellular/molecular perspective in animal models and in vitro cultures vs. scientists in the imaging community who are looking to find evidence for these mechanisms operating on a much larger scale in living humans. It is obvious that some debates at the cell level cannot be broached by human imaging approaches (e.g., whether tau spreads extracellularly or via direct connections), but it is very important to identify questions that human imaging can weigh in on. For example, a key finding in this study by Wu et al. that brain regions with higher neuronal activity might, once exposed to tau pathology, aggregate tau faster and spread it to other regions more rapidly than regions with lower activity, sounds very testable in the living human brain using imaging techniques such as tau PET and fMRI.
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