Abstract
Obesity, insulin resistance, and type 2 diabetes mellitus are associated with cognitive impairment, known as diabetic cognopathy. In this study, we tested the hypothesis that neurovascular unit(s) (NVU) within cerebral cortical gray matter regions display 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 (at 20 weeks of age), left-brain hemispheres of the DBC and age-matched non-diabetic wild-type control C57BL/KsJ (CKC) mice were immediately immersion-fixed. We found attenuation/loss of endothelial blood–brain barrier tight/adherens junctions and pericytes, thickening of the basement membrane, aberrant mitochondria, and pathological remodeling of protoplasmic astrocytes. Additionally, there were adherent red blood cells and NVU microbleeds (cortical layer III) in DBC mice, which were not observed in CKC animals. While this study represents only a “snapshot in time”, it does allow for cellular remodeling comparisons between DBC and CKC. In this paper, the first of a three-part series, we report the observational ultrastructural remodeling changes of the NVU and its protoplasmic astrocytes in relation to the surrounding neuropil. Having identified multiple abnormal cellular remodeling changes in the DBC as compared to CKC models, we will design future experiments to evaluate various treatment modalities in DBC mice.
Highlights
Type 2 diabetes mellitus (T2DM) is a chronic endocrine-metabolic disorder of glucose metabolism characterized by hyperglycemia, insulin resistance or relative lack of insulin and impaired cognition
In regards to the representation of the image data and images shared in this paper, the following factors are important for understanding our image data: three models per group were studied by transmission electronic microscopy (TEM) (n = 3 in control CKC models, and n = 3 in db/db db mice models (DBC) models)
The marked remodeling changes observed in the diabetic DBC Neurovascular unit (NVU) and their immediate surrounding regions were immediately noted, and representative comparison images were primarily chosen at varying magnifications for this paper to better illustrate and understand the marked maladaptive ultrastructure remodeling in the obese, diabetic db/db DBC models as compared to the non-obese non-diabetic CKC models
Summary
Type 2 diabetes mellitus (T2DM) is a chronic endocrine-metabolic disorder of glucose metabolism characterized by hyperglycemia, insulin resistance or relative lack of insulin and impaired cognition. Pcs are known to be contractile cells that allow for NVU capillary contraction/relaxation to permit relaxation in regions of highly active neurons, which allow for increased regional cerebral blood flow (CBF) and neurovascular coupling (NVC) with intact astrocytes. The ACs electron-dense thinned plasma membranes tightly adhere or abut the outer BMs of the ECs and Pcs. The AC completes the third key cell of the neurovascular unit; the microglia are an important part and in both the grey matter and especially the white matter oligodendrocytes become a highly important part of the NVU as well (Figure 1). Is an all-inclusive term and appears to form the background tissue along with a very thinned extracellular matrix–interstitium within the cortical grey matter, which includes the vast number of dendritic synapses, neurons (myelinated/unmyelinated axons) passing through the neuropil along with other glial cells and processes (Figure 1).
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