Tauopathy in the brain of patients with Alzheimer's disease starts in the entorhinal cortex (EC) and spreads anatomically in a defined pattern. To test whether pathology initiating in the EC spreads through the brain along synaptically connected circuits, we have generated a transgenic mouse model that differentially expresses pathological human tau in the EC and we have examined the distribution of tau pathology at different timepoints. In relatively young mice (10–11 months old), human tau was present in some cell bodies, but it was mostly observed in axons within the superficial layers of the medial and lateral EC, and at the terminal zones of the perforant pathway. In old mice (>22 months old), intense human tau immunoreactivity was readily detected not only in neurons in the superficial layers of the EC, but also in the subiculum, a substantial number of hippocampal pyramidal neurons especially in CA1, and in dentate gyrus granule cells. Scattered immunoreactive neurons were also seen in the deeper layers of the EC and in perirhinal and secondary somatosensory cortex. Immunoreactivity with the conformation-specific tau antibody MC1 correlated with the accumulation of argyrophilic material seen in old, but not young mice. In old mice, axonal human tau immunoreactivity, especially at the endzones of the perforant pathway, was greatly reduced. Relocalization of tau from axons to somatodendritic compartments and propagation of tauopathy to regions outside of the EC correlated with mature tangle formation in neurons in the EC as revealed by thioflavin-S staining. Our data demonstrate propagation of pathology from the EC and support a trans-synaptic mechanism of spread along anatomically connected networks, between connected and vulnerable neurons. In general, the mouse recapitulates the tauopathy that defines the early stages of AD and provides a model for testing mechanisms and functional outcomes associated with disease progression.

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The ubiquitin proteasome system (UPS) degrades misfolded proteins including those implicated in neurodegenerative diseases. We investigated the effects of tau accumulation on proteasome function in a mouse model of tauopathy and in a cross to a UPS reporter mouse (line Ub-G76V-GFP). Accumulation of insoluble tau was associated with a decrease in the peptidase activity of brain 26S proteasomes, higher levels of ubiquitinated proteins and undegraded Ub-G76V-GFP. 26S proteasomes from mice with tauopathy were physically associated with tau and were less active in hydrolyzing ubiquitinated proteins, small peptides and ATP. 26S proteasomes from normal mice incubated with recombinant oligomers or fibrils also showed lower hydrolyzing capacity in the same assays, implicating tau as a proteotoxin. Administration of an agent that activates cAMP–protein kinase A (PKA) signaling led to attenuation of proteasome dysfunction, probably through proteasome subunit phosphorylation. In vivo, this led to lower levels of aggregated tau and improvements in cognitive performance.

There are multiple genetic links between schizophrenia and a deficit of proline dehydrogenase (PRODH) enzyme activity. However, reports testing for an association of schizophrenia with the resulting proline elevation have been conflicting. The objectives of this study were to investigate whether hyperprolinemia is associated with schizophrenia, and to measure the relationship between plasma proline, and clinical features and symptoms of schizophrenia. We performed a cross-sectional case-control study, comparing fasting plasma proline in 90 control subjects and 64 schizophrenic patients and testing for association of mild to moderate hyperprolinemia with schizophrenia. As secondary analyses, the relationship between hyperprolinemia and five measures of clinical onset, symptoms and outcome were investigated. Patients had significantly higher plasma proline than matched controls (p<0.0001), and categorical analysis of gender adjusted hyperprolinemia showed a significant association with schizophrenia (OR 6.15, p=0.0003). Hyperprolinemic patients were significantly older at their first hospitalization (p=0.015 following correction for multiple testing). While plasma proline level was not related to total, positive or negative symptoms, hyperprolinemic status had a significant effect on length of hospital stay (p=0.005), following adjustment for race, BPRS score, and cross-sectional time from admission to proline measurement. Mild to moderate hyperprolinemia is a significant risk factor for schizophrenia, and may represent an intermediate phenotype in the disease. Hyperprolinemic patients have a significantly later age of first psychiatric hospitalization, suggestive of later onset, and hospital stays 46% longer than non-hyperprolinemic subjects. These findings have implications in the etiology of schizophrenia, and for the clinical management of these patients.

Background During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, patients with confirmed cases in New York State accounted for roughly 25% of total US cases, with psychiatric hospital in-patients at particularly high risk for COVID-19 infection. Aims The beneficial effects of mental health medications, such as selective serotonin reuptake inhibitors (SSRIs), on the severity of COVID-19 disease outcomes have been documented. Protective effects against infection have also been suggested for these medications. We therefore tested the hypothesis that medication use modifies the risk of COVID-19 infection in a long-stay, chronic in-patient psychiatry setting, where the potential for exposure was likely uniform across the facility, and where these medications were routinely prescribed. Method This was a retrospective cohort study of an adult psychiatric facility operated by the New York State Office of Mental Health. Current medication information and COVID-19 status was collected from electronic medical records for 165 people who were in-patients during the period January to July 2020, and logistic regression was employed to model the main effects of medication use on COVID-19 infection. Results A significant protective association was observed between antidepressant use and COVID-19 infection (odds ratio (OR) = 0.33, 95% CI 0.15–0.70, adjusted P < 0.05). Analysis of individual antidepressant classes showed that SSRI, serotonin-norepinephrine reuptake inhibitor and the serotonin-2 antagonist reuptake inhibitor classes of antidepressants, drove this protective effect. Exploratory analyses of individual antidepressants demonstrated an association between lower risk of infection and fluoxetine use (P = 0.023), as well as trazodone use (P = 0.001). Conclusions The novel finding of reduced COVID-19 infection risk for psychiatric in-patients taking antidepressants, suggests that antidepressants may be an important weapon in the continued fight against COVID-19 disease. This finding may become particularly salient for in-patient settings if vaccine-resistant strains of the virus appear.