Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models

Abstract

End organ injury in diabetes mellitus (DM) is driven by microvascular compromise (including diabetic retinopathy and nephropathy). Cognitive impairment is a well-known complication of DM types 1 and 2; however, its mechanism(s) is(are) not known. We hypothesized that blood-brain barrier (BBB) compromise plays a key role in cognitive decline in DM. Using a DM type 1 model (streptozotocin injected C57BL/6 mice) and type 2 model (leptin knockout obese db/db mice), we showed enhanced BBB permeability and memory loss (Y maze, water maze) that are associated with hyperglycemia. Gene profiling in isolated microvessels from DM type 1 animals demonstrated deregulated expression of 54 genes related to angiogenesis, inflammation, vasoconstriction/vasodilation, and platelet activation pathways by at least 2-fold (including eNOS, TNFα, TGFβ1, VCAM-1, E-selectin, several chemokines, and MMP9). Further, the magnitude of gene expression was linked to degree of cognitive decline in DM type 1 animals. Gene analysis in brain microvessels of DM type 2 db/db animals showed alterations of similar genes as in DM 1 model, some to an even greater extent. Neuropathologic analyses of brain tissue derived from DM mice showed microglial activation, expression of ICAM-1, and attenuated coverage of pericytes compared to controls. There was a significant upregulation of inflammatory genes in brain tissue in both DM models. Taken together, our findings indicate that BBB compromise in DM in vivo models and its association with memory deficits, gene alterations in brain endothelium, and neuroinflammation. Prevention of BBB injury may be a new therapeutic approach to prevent cognitive demise in DM.

Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model–Part II: Microglia and Mitochondria

“…Further, these aberrant mitochondria may result in damage not only to the inner membranes but also the outer mitochondrial membranes that may allow for herniation and loss of the mitochondrial matrix proteins and sometimes result in mitochondria swelling ( Figure 15) [23]. Recently, there has been an interest in hyperglycemia-driven neuroinflammation, which may compromise the integrity of BBB with increased permeability that leads to memory loss and impaired cognition [18]. This, along with the increasing interest in the vascular contributions to cognitive impairment and dementia, wherein scientific experts convened to discuss the research gaps in our understanding of how vascular factors contribute to Alzheimer's disease and related dementia has been discussed.…”

“…Recently, there has been an interest in hyperglycemia-driven neuroinflammation, which may compromise the integrity of BBB with increased permeability that leads to memory loss and impaired cognition [18]. This, along with the increasing interest in the vascular contributions to cognitive impairment and dementia, wherein scientific experts convened to discuss the research gaps in our understanding of how vascular factors contribute to Alzheimer's disease and related dementia has been discussed.…”

“…Previously, we had to include images of WBC adherence in Part I because there is such widespread multicellular remodeling that it is difficult to just examine one aspect of cellular remodeling in one image without including other cellular remodeling changes that concurrently occur in DBC models [1]. Also, these glial remodeling changes are associated with hyperglycemia and it is important to understand how hyperglycemia may drive the chronic neuroinflammation and the associated compromise of BBB TJ/AJ, which promote an increase in permeability and leads to memory loss and impaired cognition in T2DM mouse models in the diabetic DBC [18]. Activated microglia are known not only to contain certain cell surface receptors but also are responsible for the secretion of a specialized group of signaling cytokines and chemokines, which include monocyte chemoattractant protein 1 (MCP-1) chemokine also known as CCL2.…”

Disruption of the hippocampal and hypothalamic blood–brain barrier in a diet-induced obese model of type II diabetes: prevention and treatment by the mitochondrial carbonic anhydrase inhibitor, topiramate

“…In KKA y mice, a model of type II diabetes, Min et al demonstrated that blocking angiotensin II type 1 receptors to activate peroxisome proliferator-activated receptor (PPAR)-γ protected against cognitive decline by preserving the integrity of the BBB [11]. More recently, Rom et al published a paper examining BBB disruption using the fluorescent tracer, sodiumfluorescein (NaF) in the leptin receptor deficient db/ db mouse model [12]. These publications assessed BBB integrity using either non-quantitative techniques such as Evans Blue or IgG extravasation or non-reliable quantitative methods such as sodium fluorescein [13].…”

Natural products and their derivatives as multifunctional ligands against Alzheimer's disease

“…Furthermore, the clearance of βA in the brain is associated with an IDE. Therefore, development of IDE activators could be one of the possible drugable target in AD (Matioli & Nitrini, 2015;Pivovarova, Höhn, Grune, Pfeiffer, & Rudovich, 2016;Rom et al, 2019).…”