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.
Highlights
Tauopathic degenerative conditions, such as Alzheimer’s Disease (AD), are united by exhibiting transregionally spreading proteinopathy, resulting in stereotyped spatiotemporal progression patterns [5, 30, 31]
That spatiotemporal tau pathology proliferation patterns might be driven mainly by anatomic connectivity is an important finding for three reasons
It argues against the hypothesis that upstream regulators of proteinopathy are innately arranged within the brain in a manner that explains spatiotemporal tau pathology progression [12]
Summary
Tauopathic degenerative conditions, such as Alzheimer’s Disease (AD), are united by exhibiting transregionally spreading proteinopathy, resulting in stereotyped spatiotemporal progression patterns [5, 30, 31]. Graph theoretic modeling on large sets of public patient data, in particular the network diffusion (ND) model [33] and the epidemic spread model [21], Mezias et al Acta Neuropathologica Communications (2017) 5:61 suggest that connectivity with regions already exhibiting pathology predicts the unfolding pattern of atrophy and amyloid deposition, respectively. These models, which used mathematical equations to predict the spread of pathology on the brain network, significantly recreate both the cross-sectional patterns of regional volumetric loss [33] and longitudinal volumetric loss and glucose metabolic deficits [34]. Mice transgenic for only wildtype human tau (hTau) injected with proteopathic seeds show tau progression into areas heavily connected with the inoculated region [9]
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