Kaipainen, S. | bioRxiv Science

bioRxiv2020

Patient iPSC-astrocytes show transcriptional and functional dysregulation in schizophrenia

Human astrocytes are multifunctional brain cells and may contribute to the pathophysiology of schizophrenia (SCZ). We differentiated astrocytes from induced pluripotent stem cells of monozygotic twins discordant for SCZ, and found sex-specific gene expression and signaling pathway alterations related particularly to inflammation and synaptic functions. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co-twins, and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in demyelination, synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Altogether, our results show that astrocytes contribute to both familial risk and clinical manifestation of SCZ in a sex-specific manner.

neuroscience↗

bioRxiv2020

Diabetic phenotype in mouse and humans with β-amyloid pathology reduces the number of microglia around β-amyloid plaques

Type 2 diabetes (T2D) increases the risk of Alzheimers disease (AD). Even though these two diseases share common molecular pathways, the mechanisms remain elusive. To shed light into these mechanisms, mice with different AD- and/or tauopathy-linked genetic backgrounds were utilized; APPswe/PS1dE9 (A+Tw), Tau P301L (AwT+), and APPswe/PS1dE9/Tau P301L (A+T+). Feeding these mice with typical Western diet (TWD) led to obesity and diabetic phenotype as compared to respective mice with a standard diet. TWD also exacerbated memory and learning impairment in A+Tw and AwT+, but not in A+T+ mice. Furthermore, RNA sequencing of mouse hippocampal samples revealed altered responses to AD-related pathologies in A+Tw and A+T+ mice upon TWD, pointing specifically towards aberrant microglial functionality and PI3K-Akt signaling. Accordingly, fewer microglia alongside an increased number of dystrophic neurites around {beta}-amyloid plaques, and impaired PI3K-Akt signaling, were discovered in the hippocampus of TWD mice. Mechanistic elucidation revealed that disruption of the PI3K-Akt signaling pathway by pharmacological or genetic approaches significantly decreased the phagocytic uptake and proinflammatory response as well as increased the activity of Syk-kinase upon ligand-induced activation of Trem2/Dap12 signaling in mouse microglia. Finally, characterization of microglial pathology in cortical biopsies of idiopathic normal pressure hydrocephalus (iNPH) patients harboring {beta}-amyloid plaques revealed a significant decrease in the number of microglia per {beta}-amyloid plaque in obese iNPH patients with T2D as compared to both normal weight and obese iNPH patients without T2D. Collectively, these results suggest that the peripheral diabetic phenotype in mice and humans associates with reduced microglial response to {beta}-amyloid pathology.

neuroscience↗