Mechanisms of Cell-to-Cell Transmission of Pathological Tau

Abstract

IMPORTANCE Intracellular tau protein aggregates are a pathological hallmark of neurodegenerative tauopathies, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease. Emerging evidence supports a model of cell-to-cell transmission of proteinaceous pathological tau seeds, which leads to recruitment and templated fibrillization of endogenous cellular tau followed by the spread of abnormal tau throughout the brain. These findings lead to the strain hypothesis, which predicts that distinct conformational strains or polymorphs of tau may underlie the clinical and neuropathological heterogeneity and cell-type specificity of tauopathies. In this review, we describe the evidence for propagation of distinct tau strains in cell culture and animal models of AD and mechanistic insights into cell-to-cell transmission of pathological tau. OBSERVATIONS Intracranial injections of synthetic tau-preformed fibrils and human brain-derived pathological tau into nontransgenic wild-type mice and transgenic mouse models of AD expressing β-amyloid and tau-amyloid deposits yield widespread pathological tau aggregates observed in neuroanatomically connected brain regions distant from the site of injection. Furthermore, when human brain–derived pathological tau obtained from distinct tauopathies (ie, brains with AD, PSP, and CBD) were injected into the brains of wild-type mice, they seeded tau pathology and faithfully recapitulated cell-type specific tau inclusions characteristic of each tauopathy in a time-dependent, dose-dependent, and injection site–dependent spread reflective of the connectome of the injection site. CONCLUSIONS AND RELEVANCE These findings provide compelling evidence that misfolded or pathological conformers of tau undergo cell-to-cell spread in a tauopathy strain-specific manner. Importantly, evidence to date supports that pathological tau strains do not behave like infectious agents, despite growing evidence that these tau strains undergo templated propagation and spread linked to the neuroanatomical connectome of the injection site.

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

“…Our independently validated findings provide strong support for the notion that tau spreads across synaptic connections in an activity-dependent manner, as suggested by preclinical findings [14][15][16] . Our results may also motivate future studies to investigate tau spreading in other tauopathies such as primary age-related tauopathy, progressive nuclear palsy or corticobasal degeneration where tau pathology may spread via similar mechanisms [51][52][53] . Since tau is the strongest driver of cognitive decline in AD, potential interventions could target connectivity-related spreading mechanisms 16 or silencing of amyloid-induced neuronal hyperactivity that may promote tau spreading 54,55 .…”

Alzheimer’s-like pathology in aging rhesus macaques: Unique opportunity to study the etiology and treatment of Alzheimer’s disease

“…pS214Tau Traffics Between Neurons. Data from mouse models have demonstrated that phosphorylated tau can traffic within neural networks (83), for example from the ERC to "infect" hippocampal neurons (84). ImmunoEM has captured this process in the aging primate cortex, revealing pS214Tau trafficking between neurons in middle-aged ERC (7) and in aged dlPFC (40).…”

Human tau pathology transmits glial tau aggregates in the absence of neuronal tau

“…Many studies have shown that pathological tau aggregates can propagate from cell to cell through transmission of proteopathic tau seeds (Gibbons et al, 2019). Under this framework, our laboratory and others showed that different structural conformations of misfolded tau (tau strains) form in human tauopathy brains and underlie the heterogeneity of tauopathies (Clavaguera et al, 2013; Kaufman et al, 2016; Narasimhan et al, 2017; Sanders et al, 2014).…”