Tau seeds from patients induce progressive supranuclear palsy pathology and symptoms in primates

Brain. 2022 Nov 16;awac428. doi: 10.1093/brain/awac428. Online ahead of print.

Abstract

Progressive supranuclear palsy (PSP) is a primary tauopathy affecting both neurons and glia and is responsible for both motor and cognitive symptoms. Recently, it has been suggested that PSP tauopathy may spread in the brain from cell to cell in a "prion-like" manner. However, direct experimental evidence of this phenomenon, and its consequences on brain functions, is still lacking in primates. In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of PSP patients. We also isolated the same fraction from age-matched control brains. Compared to control extracts, the in vitro characterization of PSP-tau fractions demonstrated a high seeding activity in P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), misfolded, filamentous (pFTAA positive), and sarkosyl-insoluble tau. We bilaterally injected two male rhesus macaques in the supranigral area with this fraction of PSP-tau proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features revealed that PSP-tau injected macaques exhibited symptoms suggestive of parkinsonism as early as six months after injection, remaining present until sacrifice at 18 months. Object retrieval task showed the progressive appearance of a significant dysexecutive syndrome in PSP-tau injected macaques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in PSP-tau injected macaques. Characteristic pathological hallmarks of PSP, including globose and neurofibrillary tangles, tufted astrocytes, and coiled bodies, were found close to the injection sites but also in connected brain regions that are known to be affected in PSP (striatum, pallidum, thalamus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease. Our results demonstrate that PSP patient-derived tau aggregates can induce motor and behavioral impairments in non-human primates related to the prion-like seeding and spreading of typical pathological PSP lesions. This pilot study pave the way for supporting PSP-tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurodegenerative disease.

Keywords: non-human primate; parkinsonism; prion-like; progressive supranuclear palsy; tau; tauopathy.