5 research outputs found
Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport
AbstractIn Alzheimer's disease (AD), tau undergoes numerous modifications, including increased phosphorylation at serine-422 (pS422). In the human brain, pS422 tau protein is found in prodromal AD, correlates well with cognitive decline and neuropil thread pathology, and appears associated with increased oligomer formation and exposure of the N-terminal phosphatase-activating domain (PAD). However, whether S422 phosphorylation contributes to toxic mechanisms associated with disease-related forms of tau remains unknown. Here, we report that S422-pseudophosphorylated tau (S422E) lengthens the nucleation phase of aggregation without altering the extent of aggregation or the types of aggregates formed. When compared to unmodified tau aggregates, the S422E modification significantly increased the amount of SDS-stable tau dimers, despite similar levels of immunoreactivity with an oligomer-selective antibody (TOC1) and another antibody that reports PAD exposure (TNT1). Vesicle motility assays in isolated squid axoplasm further revealed that S422E tau monomers inhibited anterograde, kinesin-1 dependent fast axonal transport (FAT). Unexpectedly, and unlike unmodified tau aggregates, which selectively inhibit anterograde FAT, aggregates composed of S422E tau were found to inhibit both anterograde and retrograde FAT. Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT. Taken together, these findings identify a novel mechanistic basis by which pS422 confers upon tau a toxic effect that may directly contribute to axonal dysfunction in AD and other tauopathies
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Computerized cognitive training is associated with improved psychosocial treatment engagement in schizophrenia.
Poor treatment engagement is an enduring problem in the care of patients with schizophrenia. Evidence suggests that targeted cognitive training (TCT) improves cognition and functional outcomes, but this time-consuming intervention might reduce patients' engagement in other treatment activities when implemented in real-world settings. This is especially true of residential care programs which encourage patients to engage in group therapies, self-care, and a wide variety of structured social, work, and other rehabilitation activities. This study aimed to determine whether TCT negatively impacts engagement in other psychosocial treatments. Patients with schizophrenia were recruited from a community-based residential care program and randomized to one of two intervention arms: treatment as usual (TAU; n = 22) or TAU augmented with TCT (n = 24). Psychosocial treatment engagement was tracked over 20 weeks. Treatment groups did not significantly differ on baseline variables or psychosocial treatment engagement in the 5 weeks prior to randomization. TCT had a positive effect on engagement (β = 0.112, p = 0.003), but there was no treatment-by-time interaction (β = -0.029, p = 0.672). Participants in TCT engaged in an average of 1.34 additional group therapies, 0.58 additional activities of daily living, and 0.84 additional rehabilitation activities per week in comparison to TAU participants. Baseline cognition was also a significant predictor of psychosocial treatment engagement. Overall, results suggest that TCT can be implemented in real-world settings without negatively impacting engagement in other psychosocial treatments. Additional studies are needed to determine what role nonspecific factors play in the positive impact of TCT
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Targeted cognitive training improves auditory and verbal outcomes among treatment refractory schizophrenia patients mandated to residential care
Computerized targeted cognitive training (TCT) of auditory processing has been shown to improve verbal learning in several clinical trials of schizophrenia outpatients. Less is known, however, about the effectiveness of this promising intervention in more chronic, treatment-refractory patients who are treated in non-academic settings. This study aimed to determine whether TCT improves auditory processing, verbal learning, and clinical symptoms in SZ patients mandated to receive care at a locked residential rehabilitation center. Secondarily, potential factors that moderate TCT's effectiveness including age, symptom severity, antipsychotic medication load, and duration of illness were examined. Schizophrenia patients were randomized to treatment as usual (TAU; n = 22) or TAU augmented with TCT (TAU + TCT; n = 24). Outcomes included a measure of auditory perception (Word-In-Noise test, WIN), verbal learning domain scores from the MATRICS Consensus Cognitive Battery (MCCB), and clinical symptoms (Scale for the Assessment of Positive Symptoms, SAPS; Scale for the Assessment of Negative Symptoms, SANS). TCT produced significant improvements in auditory perception (d = 0.67) and verbal learning (d = 0.65); exploratory analyses revealed a statistically significant reduction in auditory hallucinations (d = -0.64). TCT's effects were only weakly, and mostly non-significantly, moderated by age, clinical symptoms, medication, and illness duration. These findings indicate that even highly symptomatic, functionally disabled patients with chronic illness benefit from this emerging treatment. Ongoing studies will examine the predictive utility of neurophysiological biomarkers and other characteristics assessed at baseline