Prion-like Spreading in Tauopathies

Abstract

Tau is a microtubule-associated protein that functions in regulating cytoskeleton dynamics, especially in neurons. Misfolded and aggregated forms of tau produce pathological structures in a number of neurodegenerative diseases, including Alzheimer's disease (AD) and tauopathy dementias. These disorders can present with a sporadic etiology, such as in AD, or a familial etiology, such as in some cases of frontotemporal dementia with parkinsonism. Notably, the pathological features of tau pathology in these diseases can be very distinct. For example, the tau pathology in corticobasal degeneration is distinct from that of an AD patient. A wealth of evidence has emerged within the last decade to suggest that the misfolded tau in tauopathies possesses prion-like features and that such features may explain the diverse characteristics of tauopathies. The prion-like concept for tauopathies arose initially from the observation that the progressive accumulation of tau pathology as the symptoms of AD progress seemed to follow anatomically linked pathways. Subsequent studies in cell and animal models revealed that misfolded tau can propagate from cell to cell and from region to region in the brain through direct neuroanatomical connections. Studies in these cell and mouse models have demonstrated that experimentally propagated forms of misfolded tau can exist as conformationally distinct "strains" with unique biochemical, morphological, and neuropathological characteristics. This review discusses the clinical, pathological, and genetic diversity of tauopathies and the discoveries underlying the emerging view that the unique features of clinically distinct tauopathies may be a reflection of the strain of misfolded tau that propagates in each disease.

Keywords: Alzheimer’s disease; Animal models; Prion; Strains; Tau; Transmission.

Figure 1

Representative images of (A) neurofibrillary tangles, (B) neuropil threads and (C) dystrophic neurites within a senile plaque in the hippocampus of patients with Alzheimer’s disease stained with anti-phospho tau antibody AT8. Bar = 50 μM.

Figure 2

Representative diagram of the 6 tau isoforms expressed in human adult brain due to alternative RNA splicing generated from the MAPT gene. Above is an alignment (not drawn to scale) corresponding to the MAPT exons that yield these various tau isoforms. Only the exons that be retained for expression in human brain are depicted and these are colored matched the protein regions. The amino acids are numbered according to the longest of these isoforms (441 amino acid in length). The amino-terminal inserts are identified as N1 and N2. The microtubule-binding repeats are depicted as R1–R4.

Figure 3

(A) Cartoon depicting the proposed mechanisms for the spread of tau inclusion including: tunneling nanotubes (1), endocytosis (2), plasma membrane translocation (3), receptor-mediated endocytosis (4), and exosome release and fusion (5). (B) Distinct conformations of tau strains seed aggregate formation of conformationally similar templates when exogenously administered to the CNS containing both 3R and 4R tau isoforms. All of the indicated strains could contain 0, 1, or 2 N-terminal repeats, as these regions have not been demonstrated to affect tau strain properties.