Brain mural cell loss in the parietal cortex in Alzheimer’s disease correlates with cognitive decline and TDP‐43 pathology

Neuropathology and Applied Neurobiology, Год журнала: 2020, Номер 46(5), С. 458 - 477

Опубликована: Янв. 23, 2020

Brain mural cells (BMC), smooth muscle and pericytes, interact closely with endothelial modulate numerous cerebrovascular functions. A loss of BMC function is suspected to play a role in the pathophysiology Alzheimer's Disease (AD).BMC markers, namely alpha actin (α-SMA) for cells, as well platelet-derived growth factor receptor β (PDGFRβ) aminopeptidase N (ANPEP or CD13) were assessed by Western immunoblotting microvessel extracts from parietal cortex 60 participants Religious Orders study, ages at death ranging 75 98 years old.Participants clinically diagnosed AD had lower vascular levels α-SMA, PDGFRβ CD13. These reductions correlated cognitive scores global cognition, episodic semantic memory, perceptual speed visuospatial ability. In addition, CD13 negatively Aβ40 concentrations. Vascular markers also inversely insoluble cleaved phosphorylated transactive response DNA binding protein 43 (TDP-43) (25 kDa) positively soluble TDP-43 (35 cortical homogenates, suggesting strong association between aggregation.The results this study highlight AD. The associations scores, aggregation accumulation Aβ suggest that contributes both symptoms pathology, further strengthening link defects dementia.

Язык: Английский

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Precision functional mapping of human memory systems

Current Opinion in Behavioral Sciences, Год журнала: 2021, Номер 40, С. 52 - 57

Опубликована: Фев. 1, 2021

Язык: Английский

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TrkB signaling regulates the cold-shock protein RBM3-mediated neuroprotection

Life Science Alliance, Год журнала: 2021, Номер 4(4), С. e202000884 - e202000884

Опубликована: Фев. 9, 2021

Increasing levels of the cold-shock protein, RNA-binding motif 3 (RBM3), either through cooling or by ectopic over-expression, prevents synapse and neuronal loss in mouse models neurodegeneration. To exploit this process therapeutically requires an understanding mechanisms controlling cold-induced RBM3 expression. Here, we show that increases activation TrkB via PLCγ1 pCREB signaling. RBM3, turn, has a hitherto unrecognized negative feedback on TrkB-induced ERK induction its specific phosphatase, DUSP6. Thus, mediates structural plasticity distinct, non-canonical signaling, which is abolished RBM3-null neurons. Both genetic reduction pharmacological antagonism downstream mediators abrogate cooling-induced prevent plasticity, whereas inhibition similarly neuroprotective effects prion-diseased mice. Conversely, agonism induces without cooling, preventing signaling is, therefore, necessary for related provides target RBM3-mediated synapse-regenerative therapies neurodegenerative disorders can be used need inducing hypothermia.

Язык: Английский

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Structural and compositional diversity in the kainate receptor family

Cell Reports, Год журнала: 2021, Номер 37(4), С. 109891 - 109891

Опубликована: Окт. 1, 2021

The kainate receptors (KARs) are members of the ionotropic glutamate receptor family and assemble into tetramers from a pool five subunit types (GluK1-5). Each confers distinct functional properties to receptor, but compositional stoichiometric diversity KAR is not well understood. To address this, we first solve structure GluK1 homomer, which enables systematic assessment structural compatibility among subunits. Next, analyze single-cell RNA sequencing data, reveal extreme in combinations two or more subunits co-expressed within same cell. We then investigate composition individual complexes using single-molecule fluorescence techniques find that di-heteromers assembled GluK1, GluK2, GluK3 can form with all possible stoichiometries, while GluK1/K5, GluK2/K5, GluK3/K5 3:1 2:2 complexes. Finally, three-color imaging, discover KARs tri- tetra-heteromers.

Язык: Английский

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Advances in tethered photopharmacology for precise optical control of signaling proteins

Current Opinion in Pharmacology, Год журнала: 2022, Номер 63, С. 102196 - 102196

Опубликована: Март 2, 2022

Язык: Английский

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