Connectivity, not region-intrinsic properties, predicts regional vulnerability to progressive tau pathology in mouse models of disease

Abstract

Spatiotemporal tau pathology progression is regarded as highly stereotyped within each type of degenerative condition. For instance, AD has a progression of tau pathology consistently beginning in the entorhinal cortex, the locus coeruleus, and other nearby noradrenergic brainstem nuclei, before spreading to the rest of the limbic system as well as the cingulate and retrosplenial cortices. Proposed explanations for the consistent spatial patterns of tau pathology progression, as well as for why certain regions are selectively vulnerable to exhibiting pathology over the course of disease generally focus on transsynaptic spread proceeding via the brain’s anatomic connectivity network in a cell-independent manner or on cell-intrinsic properties that might render some cell populations or regions uniquely vulnerable. We test connectivity based explanations of spatiotemporal tau pathology progression and regional vulnerability against cell-intrinsic explanation, using regional gene expression profiles as a proxy. We find that across both exogenously seeded and non-seeded tauopathic mouse models, the connectivity network provides a better explanation than regional gene expression profiles, even when such profiles are limited to specific sets of tau risk-related genes only. Our results suggest that, regardless of the location of pathology initiation, tau pathology progression is well characterized by a model positing entirely cell-type and molecular environment independent transsynaptic spread via the mouse brain’s connectivity network. These results further suggest that regional vulnerability to tau pathology is mainly governed by connectivity with regions already exhibiting pathology, rather than by cell-intrinsic factors.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0459-z) contains supplementary material, which is available to authorized users.

Analysis of Amyloid-β Pathology Spread in Mouse Models Suggests Spread Is Driven by Spatial Proximity, Not Connectivity

“…In the present study, we hope to add clarity to the amyloid-β pathology spread debate by analyzing available data on the patterns of regional amyloid pathology severity and spatiotemporal progression in mouse models. We first demonstrate amyloid-β pathology patterns in mouse models are not mirrored by the mouse connectome, while those of tau pathology, accordant with prior research ( 16 ), are. Furthermore, a model of connectivity-based amyloid-β pathology spread fails to recreate spatiotemporal patterns of amyloid-β pathology development in a mouse model.…”

“…Prior use of the brain connectome graph metrics and models (such as DNT and NT) have successfully, characterized the spatiotemporal development of regional volume loss ( 2 ) and metabolic deficits ( 3 ) in patients, and the spatiotemporal proliferation of tau pathology in mouse models ( 16 ). We use the first two eigenvectors of the mouse brain connectome to assess whether amyloid-β pathology can be recapitulated by the properties of mouse brain wiring in a way that resembles the accurate characterization of tau pathology.…”

“…For example, a whole litany of patient ( 3 , 10 ) and mouse model-based ( 11 – 15 ) studies has looked at whole brain and cellular level resolutions and determined that the evidence, regardless of resolution of study, is most consistent with a transsynaptic and intracellular mechanism of tau spread. In fact, our own recent research demonstrates that tau pathology in mouse models progression mirrors the network of mouse fiber tracts ( 16 ). Similarly, regarding α-synuclein, there is strong evidence pointing toward transsynaptic and intracellular mechanisms of spread, including transfer of pathology from Parkinson’s and LBD patient neurons into grafted and implanted cells ( 17 ), the presence of both misfolded and normal state α-synuclein at the synapse ( 18 ), and controlled cell-to-cell transfer experiments in mice ( 18 ) demonstrating that α-synuclein spread occurs transsynaptically by virtue of initiation into a set of interconnected cells.…”

Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

“…Post-mortem histopathological analyses (Braak and Braak, 1991; Braak et al, 2003; Brettschneider et al, 2013) and in vivo imaging studies (Deng et al, 2004; Poudel et al, 2019) indicate that proteopathic lesions associated with neurodegeneration appear in highly-reproducible and disease-specific spatiotemporal patterns through the brain. Interestingly, these patterns largely follow neuroanatomical tracts (Ahmed et al, 2014; Mezias et al, 2017), suggesting a central role for synaptic connectivity in pathological aggregate spreading. Accumulating evidence supports the idea that intracellular aggregates formed by tau, α-synuclein, TDP-43, SOD1, and mutant huntingtin (mHtt) transfer from cell-to-cell and self-replicate by recruiting natively-folded versions of the same protein, analogous to how infectious prion protein (PrP Sc ) templates the conformational change of soluble PrP C in prion diseases (Vaquer-Alicea and Diamond, 2019).…”

Matrix Inversion and Subset Selection (MISS): A novel pipeline for mapping of diverse cell types across the murine brain

“…The spatially varying abundances of cell types considered selectively vulnerable to tau or synuclein inclusions can be mapped using MISS, and their correspondence with the spatial pattern of protein pathologies can be tested. While regional gene expression profiles did not seem especially predictive in a prior analysis 44 , other experiments suggest cell type selectivity of tau pathology [45][46][47] . Cellular vulnerability in other neurological conditions can also be interrogated using MISS, including psychiatric diseases such as schizophrenia 48 , and traumatic brain injury (TBI), which was hypothesized to preferentially involve certain types of cells in both injury and recovery phases 49,50 .…”