Abstract
Obesity, insulin resistance, and type 2 diabetes mellitus are associated with diabetic cognopathy. This study tested the hypothesis that neurovascular unit(s) (NVU) within cerebral cortical gray matter regions may depict abnormal cellular remodeling. The monogenic (Leprdb) female diabetic db/db [BKS.CgDock7m +/+Leprdb/J] (DBC) mouse model was utilized for this ultrastructural study. Upon sacrifice (20 weeks), left-brain hemispheres of the DBC and age-matched nondiabetic control C57BL/KsJ (CKC) mice were immediately immersion-fixed. We observed an attenuation/loss of endothelial blood–brain barrier tight/adherens junctions and pericytes, thickened basement membranes, adherent red and white blood cells, neurovascular unit microbleeds and pathologic remodeling of protoplasmic astrocytes. In this second of a three-part series, we focus on the observational ultrastructural remodeling of microglia and mitochondria in relation to the NVU in leptin receptor deficient DBC models. This study identified novel ultrastructural core signature remodeling changes, which consisted of invasive activated microglia, microglial aberrant mitochondria with nuclear chromatin condensation and adhesion of white blood cells to an activated endothelium of the NVU. In conclusion, the results implicate activated microglia in NVU uncoupling and the resulting ischemic neuronal and synaptic damage, which may be related to impaired cognition and diabetic cognopathy.
Highlights
We have overviewed the background, and documented the observations of the 20-week old female db/db [BKS.CgDock7m +/+Leprdb/J] (DBC) and its comparison to the age-matched control (CKC) model with a focus on ultrastructure protoplasmic astrocyte remodeling in relation to the neurovascular unit (NVU) [1]
We demonstrated marked multicellular ultrastructure remodeling comprised by the following: (i) attenuation and/or loss of blood–brain barrier tight and adherens junctions (TJ/AJ); adherent red blood cells to endothelial cell(s) (EC) of the NVU; microbleeds of the NVU; endothelial cell thinning and activation with white blood cell adherence to
Microglial cells reside throughout the brain parenchyma and are frequently adjacent to the endothelial cell, pericytes, mural cells and astrocytes of the NVU in the cortical grey matter of layer III
Summary
We have overviewed the background, and documented the observations of the 20-week old female db/db [BKS.CgDock7m +/+Leprdb/J] (DBC) and its comparison to the age-matched control (CKC) model with a focus on ultrastructure protoplasmic astrocyte remodeling in relation to the neurovascular unit (NVU) [1]. Microglia are unique from bone marrow derived peripheral monocyte-macrophage cells in that they are not dependent on recruitment from the peripheral systemic circulation but are capable of undergoing proliferation mechanisms if needed [13] Microglia may play both a protective role of surveillance for injury to the NVU unit (Figure S2, Figure S3 and Video S2) as well as a possible damaging role to the NVU in the DBC models due to microglia invasiveness with resulting detachment and separation of protoplasmic astrocytes from the BM of the endothelial cells and pericytes of the NVU [1]. Microglia in CKC animals display distinct phenotypes in transmission electron microscopy (TEM) (Joel 1400-EX TEM JOEL (JOEL, Peabody, MA, USA) images and these cells will be referred to as ramified microglial cells (rMGC) These cells survey their surrounding milieu of endothelial cells, pericytes, asNteruorogcliya 2t0e18s, 1 of the NVU and neurons. 14; IL-10: interleukin 10; TGF-β: Transforming growth factor beta; TNFα: tumor necrosis factor alpha; IL-6: interleukin 6; NADPH Ox: reduced nicotinamide adenine dinucleotide phosphate; Inos: inducible nitric oxide synthase; GSH: glutathione; SOD: superoxide dismutase
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