No abstract

Abnormal tau phosphorylation resulting in detachment of tau from microtubules and aggregation are critical events in neuronal dysfunction, degeneration, and neurofibrillary pathology seen in Alzheimer's disease. Glycogen synthase kinase3b (GSK3b) is a key target for drug discovery in the treatment of Alzheimer's disease and related tauopathies because of its potential to abnormally phosphorylate proteins and contribute to synaptic degeneration. We report the discovery of AZD1080, a potent and selective GSK3 inhibitor that demonstrates peripheral target engagement in Phase 1 clinical studies. AZD1080 inhibits tau phosphorylation in cells expressing human tau and in intact rat brain. Interestingly, subchronic but not acute administration with AZD1080 reverses MK-801-induced deficits, measured by long-term potentiation in hippocampal slices and in a cognitive test in mice, suggesting that reversal of synaptic plasticity deficits in dysfunctional systems requires longer term modifications of proteins downstream of GSK3b signaling. The inhibitory pattern on tau phosphorylation reveals a prolonged pharmacodynamic effect predicting less frequent dosing in humans. Consistent with the preclinical data, in multiple ascending dose studies in healthy volunteers, a prolonged suppression of glycogen synthase activity was observed in blood mononuclear cells providing evidence of peripheral target engagement with a selective GSK3 inhibitor in humans.

Our study fills an important knowledge gap in how acid treatment affects PLT function and interactions with immune cells, paving the way for controlled clinical trials to evaluate acid-treated PLTs as an alternative to HLA-matched donors in PLT refractoriness.

Objective: Lithium, a first-line drug for the treatment of bipolar depression, has recently been shown to regulate glycogen synthase kinase-3 (GSK-3), a kinase that is involved in the phosphorylation of the tau protein. Since hyperphosphorylation of tau is a core pathological feature in Alzheimer's disease, lithium-induced inhibition of GSK-3 activity may have therapeutic effects in Alzheimer's disease. In the current study, we tested the effect of short-term lithium treatment in patients with Alzheimer's disease. Method: A total of 71 patients with mild Alzheimer's disease (Mini-Mental State Examination score ≥ 21 and ≤ 26) were successfully randomly assigned to placebo (N = 38) or lithium treatment (N = 33) at 6 academic expert memory clinics. The 10-week treatment included a 6-week titration phase to reach the target serum level of lithium (0.5-0.8 mmol/L). The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and GSK-3 activity in lymphocytes. Secondary outcome measures were CSF concentration of total tau and β-amyloid 1-42 (Aβ 1-42), plasma levels of Aβ 1-42 , Alzheimer's Disease Assessment Scale (ADAS)-Cognitive summary scores, MMSE, and Neuropsychiatric Inventory (NPI). Patients were enrolled in the study from November 2004 to July 2005. Results: No treatment effect on GSK-3 activity or CSF-based biomarker concentrations (P > .05) was observed. Lithium treatment did not lead to change in global cognitive performance as measured by the ADAS-Cog subscale (P = .11) or in depressive symptoms. Conclusions: The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer's disease target population.

Neutropenia as an isolated clinical finding may include aetiologies ranging from severe disease to a transient condition, and differential diagnosis may be challenging. Previous data and clinical experience suggest that low levels of the neutrophil‐derived protein human 18 kDa cathelicidin antimicrobial protein (hCAP‐18) in the blood are predictive of more severe forms of neutropenia. The objective of this study was to present the results from a newly developed ELISA method that has been used in clinical routine in Sweden since 2018 for quantification of hCAP‐18 in blood plasma. Using this method, we report that patients with severe disease analysed during the study period presented with low or undetectable levels of blood plasma hCAP‐18, validating its use as screening tool for severe neutropenia. Furthermore, neutropenic patients as a group displayed lower levels of hCAP‐18 as compared to blood donors. Within the group of neutropenic patients, those with neutrophil antibodies displayed significantly higher hCAP‐18 levels compared to patients with idiopathic neutropenia. By including an analysis of hCAP‐18 in the primary investigation of neutropenia, an increased accuracy in differential diagnosis is achieved, thus contributing to reduced costs of neutropenia management.