Prion-Like Propagation Mechanisms in Tauopathies and Traumatic Brain Injury: Challenges and Prospects

Abstract

The accumulation of tau protein in the form of filamentous aggregates is a hallmark of many neurodegenerative diseases such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). These dementias share traumatic brain injury (TBI) as a prominent risk factor. Tau aggregates can transfer between cells and tissues in a "prion-like" manner, where they initiate the templated misfolding of normal tau molecules. This enables the spread of tau pathology to distinct parts of the brain. The evidence that tauopathies spread via prion-like mechanisms is considerable, but work detailing the mechanisms of spread has mostly used in vitro platforms that cannot fully reveal the tissue-level vectors or etiology of progression. We review these issues and then briefly use TBI and CTE as a case study to illustrate aspects of tauopathy that warrant further attention in vivo. These include seizures and sleep/wake disturbances, emphasizing the urgent need for improved animal models. Dissecting these mechanisms of tauopathy progression continues to provide fresh inspiration for the design of diagnostic and therapeutic approaches.

Keywords: clearance; concussion; dementia; prionoid; proteinopathies; seeding; strains; tau genetics; transmission.

Figure 1

The human MAPT gene, tau isoforms in the human brain, structure, and mutations. (A). Schematic of the MAPT gene on chromosome 17q21.31 which compromises 16 exons [10,31]. There are six main isoforms of tau that are generated from the alternative splicing of E2, E3, and E10. The splicing of E2 and E3 generates isoforms containing either 0, 1, or 2 amino-terminal inserts of 29 amino acids known as 0N, 1N, and 2N, respectively. The presence or absence of the second repeat R2 domain (light purple), which is encoded by exon 10, categorize the isoforms with 3R or 4R [32]. (B). Tau major domains are divided into the projection domain and the assembly repeat domain in the carboxy-terminal sections separated by a proline-rich region. The projection domain comprises residues 1–197 and is not directly involved in microtubule (MT) binding. The proline-rich region is subdivided into P1 and P2, separated by the chymotryptic cleavage site at residue 198 that divides the assembly and projection domain [33,34]. The C-terminal assembly domain is important for MT binding and assembly. The assembly domain contains the MT binding repeat region followed by a flanking region that shows a weak sequence similarity to the repeat domain [33]. The four repeats, around 30–31 residues each, are labeled R1-R4. Both P2 and the flanking regions contribute to MT assembly and binding. The MT repeat region also contains the “paired-helical filament core”, which serves as a principal structure for forming tau aggregates [35,36]. Within this structure, two hexapeptide motifs [37] important for aggregation have been highlighted in gray. Major disease-associated missense mutations that alter the sequence are also labeled.

Figure 2

Possible tau structures. (A) The proposed “Paper-clip” structure of tau, in which both the N and C terminals are closely associated [141]. However, when tau is bound to microtubules, the two terminals are separated with the N-terminal projected away from the microtubules [124]. (B) In AD tau filaments, part of the tau repeat region (R3 and R4) forms the core of the filaments while R1, R2, and both N and C terminals form the “fuzzy coat” structure that surrounds the core (based on the Cryo-EM structure described in [58]).

Figure 3

Various hypothesized mechanisms involved in the prion-like spreading of tau pathology between adjacent or nearby cells (inspired by figures in [282,283]). The mechanisms include the spread of tauopathy seeds between adjacent cells. (A) Tau aggregates inside neurons can spread from the donor (pre-synaptic) to recipient neurons (post-synaptic) via various mechanisms. Donor cell: (1) Regulated release via either soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent exocytosis, endo-lysosomal pathways mediated by Rab7, or EB proteins; (2) direct secretion via plasma-membrane (PM) translocation that includes the clustering of tau at the PM, interactions with specific lipids and release from the PM guided by HSPG cell-surface receptors; (3) intercellular transfer between neurons via tunneling nanotubes; (4) the fusion of multivesicular bodies (MVB) to plasma membranes and secretion of tau aggregates in exosomes; (5) the release of tau aggregates in ectosomes. At the recipient cell(s), released tau aggregates can be taken up by various mechanisms, including (6) receptor-mediated endocytosis (HSPGs and APP), (7) macropinocytosis, or dynamin-dependent endocytosis. The process by which cells take up exosomes and ectosomes is still unclear.

Figure 4

Various hypothesized mechanisms and vectors of the prion-like spreading of tau pathology between tissues. (A) Tau can be phagocytosed by microglia, transported, and then released via exosomes, which contribute to the spreading of tau pathology. Tau can be internalized by non-neuronal cells, such as (B) astrocytes or (C) oligodendrocytes, which contribute to glial tau transmission in tauopathies other than AD such as CBD and PSP. (D) One of the recently studied mechanisms that may account for the spread of tau pathology is the glymphatic system’s involvement (the structural organization of panel D is inspired by schematics in [284,285,286]). In this system, free tau can be cleared from the ISF using the CSF influx into the extracellular spaces within the brain parenchyma. The CSF influx flows directionally through the aquaporin four (AQP4) channel (colored in pink) [205] that is highly expressed in the end-feet of astrocytes lining the arterial and venous perivascular spaces (described in [204]). Various factors that may affect tau spreading and aggregation also need to be considered, including (E) the role of seizures, (F) synaptic connectivity and transmission, and (G) sleep/wake cycles and disruptions. Investigating these mechanisms, vectors, and factors impacting tauopathy progression is a priority area and urgently requires improved animal models of disease.