Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease.

Dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A) is known to phosphorylate the microtubule-associated tau protein. Overexpression is correlated with tau hyperphosphorylation and neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). This study assessed the potential of SM07883, an oral DYRK1A inhibitor, to inhibit tau hyperphosphorylation, aggregation, NFT formation, and associated phenotypes in mouse models. Exploratory neuroinflammatory effects were also studied. SM07883 specificity was tested in a kinase panel screen and showed potent inhibition of DYRK1A (IC50  = 1.6 nM) and GSK-3ß (IC50  = 10.8 nM) kinase activity. Tau phosphorylation measured in cell-based assays showed a reduction in phosphorylation of multiple tau epitopes, especially the threonine 212 site (EC50  = 16 nM). SM07883 showed good oral bioavailability in multiple species and demonstrated a dose-dependent reduction of transient hypothermia-induced phosphorylated tau in the brains of wild-type mice compared to vehicle (47%, p < 0.001). Long-term efficacy assessed in aged JNPL3 mice overexpressing the P301L human tau mutation (3 mg/kg, QD, for 3 months) exhibited significant reductions in tau hyperphosphorylation, oligomeric and aggregated tau, and tau-positive inclusions compared to vehicle in brainstem and spinal cord samples. Reduced gliosis compared to vehicle was further confirmed by ELISA. SM07883 was well tolerated with improved general health, weight gain, and functional improvement in a wire-hang test compared to vehicle-treated mice (p = 0.048). SM07883, a potent, orally bioavailable, brain-penetrant DYRK1A inhibitor, significantly reduced effects of pathological tau overexpression and neuroinflammation, while functional endpoints were improved compared to vehicle in animal models. This small molecule has potential as a treatment for AD.

Tactile processing in children and adolescents with obsessive-compulsive disorder.

Many obsessive-compulsive disorder (OCD) patients experience sensory phenomena, such as bodily sensations and "just-right" perceptions accompanying compulsions. We studied tactile processing in OCD by psychophysical experiments targeting the somatosensory cortex. Thirty-two children and adolescents with OCD (8 tic-related, 19 with sensory phenomena (SP)) and their sex- and age-matched controls participated in the study. After clinical assessments, two questionnaires were completed for sensory problems (Sensory Profile and Touch Inventory for Elementary-School-Aged Children). The psychophysical experiments consisted of five tasks: simple reaction time, choice reaction time, dynamic (detection) threshold, amplitude discrimination, and amplitude discrimination with single-site adaptation. The tactile stimuli were sinusoidal mechanical vibrations (frequency: 25 Hz) applied on the fingertips. Just-noticeable differences (JNDs) were found in amplitude discrimination tasks. There was no difference between the OCD group and controls in detection thresholds. However, the OCD group (especially young males) had worse amplitude discrimination (i.e., higher JNDs) than controls. Young OCD participants had reduced adaptation than young controls. Tic-related OCD participants and those with SP had higher detection thresholds than those without. Additionally, the OCD group reported more problems than controls in the Emotional/Social subset of the Sensory Profile questionnaire. The discrimination results show altered tactile processing in OCD at suprathreshold levels. This can be explained by a scaling factor modifying the sensory signal with decreasing slope at higher input levels to achieve normal Weber fractions internally. Quadratic discriminant analysis gave the best positive (76%) and negative (60%) predictive values for classifying individuals (into "OCD" or "control" groups) based on psychophysical data alone.