Does the Anti‐Tau Strategy in Progressive Supranuclear Palsy Need to Be Reconsidered? No

Abstract

Progressive supranuclear palsy (PSP) has been initially described as a neurodegenerative disease of unknown etiology, affecting the brain stem, basal ganglia, and cerebellum, leading to supranuclear gaze palsy, dysarthria, dysphagia, dystonic rigidity of the neck and upper trunk, postural instability, and a mild degree of dementia. Meanwhile, the clinical spectrum and neurodegenerative changes in PSP have been more precisely described. The neurobiological definition of PSP has emerged to focus a unique neuropathological pattern characterized by formation of insoluble aggregates composed mainly of 4-repeat isoforms of the microtubule-associated protein tau in the shape of globose neurofibrillary tangles, neuropil threads, oligodendroglial coiled bodies, and specifically tufted astrocytes. The predominance of 4-repeat tau aggregates led to the joint classification of a group of neurodegenerative diseases, including but not limited to PSP, corticobasal degeneration, argyrophilic grain disease, and globular glial tauopathies, as 4R-tauopathies. Because of their rapid clinical progression and the limited symptomatic therapeutic options available, there is a high unmet medical need to develop disease-modifying therapies for 4R-tauopathies. The temporal and anatomical distribution of tau pathology in PSP appears to follow characteristic patterns and sequential stages, suggesting a propagation of tau pathology along axonal tracks. Because brain homogenates from patients with PSP can induce tau pathology in transgenic mice expressing wild-type human tau, a prion-like propagation of spreading-competent tau species via the extracellular cerebral compartment has been assumed to constitute an important disease mechanism in PSP and other tauopathies. Therefore, 2 recent, sufficiently powered, randomized, controlled trials in PSP tested the hypothesis that passive immunization using monoclonal antibodies targeting the N-terminus of tau would be efficacious to block the spreading of tau pathology and the associated disease progression. The antibody BIIB092 (gosuranemab), a humanized version of a murine antibody raised to target tau released from induced pluripotent stem cells from a familial patient with Alzheimer’s disease, has been shown to strikingly reduce the concentration of free tau in the cerebrospinal fluid but failed to slow down the progression of clinical disease severity in a phase 2 trial. Also, the antibody ABBV-8E12 (tilavonemab), a humanized version of a mouse monoclonal antibody raised against full-length human tau, failed to show clinical efficacy in a phase 2 trial. Therefore, the concept to target tau to develop diseasemodifying therapies has been challenged. Although this series of unmet endpoints is painfully perceived as a drawback for the field, the results need to be put into the right perspective to avoid inordinate conclusions that risk to overshoot the mark, thereby preventing progress into the very right direction. First, PSP is a primary 4-repeat tauopathy from a neuropathological perspective. There is no pathogen other than tau identified in PSP that would sufficiently explain neuronal dysfunction and death and subsequent neurological deficits. In a recent clinicopathological case series, we concluded after exhaustive characterization of potential alternative pathological features in the brains of PSP patients that copathology in PSP, albeit present not infrequently, does not sufficiently explain presence and progression of clinical symptoms in PSP. Primary dysfunction of tau, on the contrary, is well proven to be sufficient to explain progressive neuronal dysfunction and degeneration, as evidenced by mutations in the tau gene MAPT with an autosomal dominance trait pattern. Because the overwhelming majority of PSP cases are sporadic, mutations with loss-of-function or gain-of-function consequences for the protein product do not obviously explain the pathogenesis