Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model—Part III: Oligodendrocyte and Myelin

Hayden, Melvin R.; Grant, DeAna G.; Aroor, Annayya R.; DeMarco, Vincent G.

doi:10.3390/neuroglia1020024

Cited by 13 publications

(47 citation statements)

References 28 publications

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“…As mentioned earlier in section 1.2, obesity seems to be the driver of both the Hyper "H" and "E" phenomenon and the Met S. (Fig.2, 3 In this figure we propose that these above precursors are more of a continuum of progression from various stages, one to the next; however, some have posited that they could each represent separate pathologies that may be differentially expressed over time and thus, remain age-related . The three boxes on the right side of this figure refer to our independent findings in the brains of the diet induced obesity, insulin resistant model with impaired glucose tolerance or prediabetes Western mouse model [8], the streptozotocin induced type 1 diabetic mouse model [9] and the db/db mouse model of obesity, insulin resistance and T2DM [4][5][6][7]. Note the intersects between #10 in Box 2 to the red dashed outline protected these NVU remodeling changes as well as increased permeability [9].…”

Section: Obesitymentioning

confidence: 95%

“…is a result of the relative or complete impairment of insulin actions, signaling, and associated with a progressive decline in pancreatic beta cell function [4,5,6,7,8,9,11,12,13,14,15,16].…”

Section: T2dm Late -Onset Alzheimer's Disease-dementia (Load) and Somentioning

confidence: 99%

“…Note the intersects between #10 in Box 2 to the red dashed outline protected these NVU remodeling changes as well as increased permeability [9]. The most recent model studied was the obese, insulin resistant, T2DM female db/db mouse model [4][5][6][7]. This model demonstrated marked NVU, microglia cell(s) (MGC) and oligodendrocyte(s) OL and myelin remodeling that was protected utilizing a 10-week treatment period with the glucose lowering antidiabetic sodium glucose transporter 2 (SGLT2) inhibitor from 10 -20 weeks of age [7].…”

Section: Obesitymentioning

confidence: 99%

“…Thus, the db/db model [4][5][6][7] was able to 'fill-in' many of our gaps in knowledge between the dietinduced obesity Western model [8] Peer-reviewed version available at Brain Sci. 2019, 9, 262; doi:10.3390/brainsci9100262…”

Section: Obesitymentioning

confidence: 99%

“…Additionally, there are mural vascular cells coursing throughout the brain consisting of endothelial cell(s) (EC), pericyte(s) (Pcs) and vascular smooth muscles cells. Each of these cells have multiple unique identifying ultrastructural forms and functions [4][5][6][7][8][9]. This review focuses on type 2 diabetes mellitus (T2DM) and the increased risk of late-onset Alzheimer's disease (LOAD) and the capillary neurovascular unit(s) (NVU) and neuroglia.…”

Section: Introductionmentioning

confidence: 99%

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Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Hayden¹

2019

Preprint

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Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

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Section: Obesitymentioning

confidence: 95%

Section: T2dm Late -Onset Alzheimer's Disease-dementia (Load) and Somentioning

confidence: 99%

Section: Obesitymentioning

confidence: 99%

Section: Obesitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Hayden¹

2019

Preprint

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Evidence for glia‐mediated, age‐dependent remodeling of myelin at the axon initial segment

Furusho,

Terasaki

2024

J of Comparative Neurology

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Due to its proximity to the axon initial segment (AIS), the paranode of the first myelin segment can influence the threshold for action potentials and how a neuron participates in a neuronal circuit. Using serial section electron microscopy, we examined its three‐dimensional (3D) organization in the ventral horn of the mouse spinal cord. The myelin loops of postnatal day 18 mice resemble those at the node of Ranvier. However, in 3‐month‐old mice, 13 of 22 para‐AIS showed 4 types of alteration: (A) A cytoplasmic foot process, with ultrastructural characteristics of an astrocyte, was interposed between the axolemma and the myelin loops. (B) A thin extension of the inner tongue was present between the foot process and axolemma. (C) The foot process was absent. The inner tongue extension was a broad lamella from which a thin extension reached beyond the loops and spiraled around axon. (D) One set of loops was adjacent to the axon, and another was further back and underlain by compact myelin. We suggest that (A)–(C) are steps in a progression toward (D). In this progression, a glial process displaces the original loops, the inner tongue reactivates and extends beneath the foot process, then wraps around the axon to form a new set of loops. This is the first study of the 3D organization of myelin at the AIS and provides evidence for glia‐mediated age‐dependent remodeling at this critical region.

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Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice

et al. 2020

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Background Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus. Methods Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated. Results Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer. Conclusions Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.

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Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model—Part III: Oligodendrocyte and Myelin

Cited by 13 publications

References 28 publications

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Evidence for glia‐mediated, age‐dependent remodeling of myelin at the axon initial segment

Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice

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