Hanseeuw, B. J. | Search bioRxiv

bioRxiv2026

Stage-dependent tau post-translational modifications map the spatiotemporal progression of Alzheimer's disease

Alzheimers disease (AD) is defined by progressive tau aggregation, yet the molecular events driving this process remain poorly understood. Post-translational modifications (PTMs) are key regulators of tau biology and potential biomarkers of disease progression. Using immunoprecipitation-mass spectrometry and absolute quantification of tau isoforms, we profiled tau PTMs in soluble and insoluble brain fractions. We studied multiple brain regions (hippocampus, inferior temporal and frontal gyri), representing regions affected at different stages of pathology, from human donors spanning the AD spectrum and staged by ABC neuropathological scoring. We uncovered a stage-dependent PTM landscape across AD progression: early phosphorylation changes, including pT217 and pS262, precede later ubiquitination events, such as uK311, associated with tau aggregation. We also identified PTMs negatively correlated with aggregation, including mK258, suggesting potential protective roles. These findings refine our understanding of the spatiotemporal evolution of tau biochemistry and offer mechanistic and translational insights into AD tauopathy.

neuroscience↗

bioRxiv2023

Impairments of motor adaptation in Essential Tremor are linked to movement execution

0.Essential tremor (ET) is a neurological disorder characterized by involuntary oscillations of the limbs. Previous studies have hypothesized that ET was a cerebellar disorder and reported impairments in motor adaptation. However, recent advances have highlighted that motor adaptation involved several components linked to anticipation and control, all dependent on cerebellum, and the specific alteration of adaptation of ET has not been identified. To address this question we investigated behavioural markers of adaptation in ET patients (n=20) and age-matched healthy volunteers (n=20) in saccadic and upper limb adaptation tasks, probing compensation for target jumps and for velocity-dependent force fields, respectively. We found that both groups adapted their movements to the novel contexts, however, ET patients adapted to a lesser extent compared to healthy volunteers. Importantly, we decomposed movements into components linked to anticipation, preserved here, and real-time execution, which were responsible for the adaptation deficit. Altogether, our results suggest that execution deficits may be a specific functional consequence of the alteration of neural pathways associated with ET. Significance StatementWe tested Essential Tremor patients adaptation abilities in classical tasks including saccadic adaptation to target jumps and reaching adaptation to force field disturbances. Patients adaptation was present but impaired in both tasks. Interestingly, the deficits were mainly present during movement execution, while the anticipatory components of movements were similar to healthy volunteers. These findings reinforce the hypothesis of a cerebellar origin for essential tremor and details the motor adaptation impairments previously found in this disorder.

neuroscience↗