Long-term central pathology and cognitive impairment are exacerbated in a mixed model of Alzheimer’s disease and type 2 diabetes

Infante-Garcia, Carmen; Ramos-Rodríguez, Juan José; Galindo-Gonzalez, Lucia; García-Alloza, Mónica

doi:10.1016/j.psyneuen.2015.12.001

Cited by 52 publications

(106 citation statements)

References 51 publications

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“…Hemorrhage burden was significantly increased in the cortex from db/db mice, as previously shown (25) and this effect was completely reversed by long-term MGF treatment [F(3,114) 5 12.70, **P < 0.01 vs. rest of the groups]. We also observed that increased hemorrhage burden was because of the larger hemorrhage densities …”

Section: Spontaneous Bleeding In Db/db Mice Is Reversed By Long-term supporting

confidence: 88%

“…Additionally, T2D animal models present increased tau phosphorylation, brain atrophy, enlarged central inflammation or spontaneous bleeding, responsible for cognitive alterations (40), in a similar way to that observed in AD and VaD. Moreover, these effects are synergistically worsened when both AD and T2D coexist (25,41,52).…”

Section: Introductionmentioning

confidence: 73%

“…Moreover, people with diabetes have more than double the risk of ischemic stroke and prolonged hyperglycemia is associated with microvascular complications [for review see (30)]. Inflammation is exacerbated in diabetic mice (9,25), as well as in T2D patients (49), and it may underlie observed vascular damage (47,50). Inflammation is exacerbated in diabetic mice (9,25), as well as in T2D patients (49), and it may underlie observed vascular damage (47,50).…”

Section: Discussionmentioning

confidence: 99%

“…Consecutive sections to the ones used for cresyl violet staining were processed as previously described (25). Consecutive sections to the ones used for cresyl violet staining were processed as previously described (25).…”

Section: Cresyl Violet and Prussian Blue Stainingmentioning

confidence: 99%

“…It has been suggested that T2D associated inflammation and vascular damage may explain its implication in the development of AD and VaD. Moreover, these effects are synergistically worsened when both AD and T2D coexist (25,41,52). Insulin receptors localize in the cortex and hippocampus, explaining its role in learning and memory.…”

Section: Introductionmentioning

confidence: 99%

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Mango leaf extract improves central pathology and cognitive impairment in a type 2 diabetes mouse model

et al. 2016

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Epidemiological studies reveal that metabolic disorders, and specifically type 2 diabetes (T2D), are relevant risk factors to develop Alzheimer's disease (AD) and vascular dementia (VaD), the most common causes of dementia. AD patients are in a tremendous need of new therapeutic options because of the limited success of available treatments. Natural polyphenols, and concretely Mangifera indica Linn extract (MGF), have been reported to have antiinflammatory, antioxidant and antidiabetic activities. The role of MGF in central complications associated with T2D, after long-term treatment of db/db mice with MGF was analyzed. Metabolic parameters (body weight, glucose and insulin levels) as well as central complications including brain atrophy, inflammatory processes, spontaneous bleeding, tau phosphorylation and cognitive function in db/db mice treated with MGF for 22 weeks were assessed. MGF limits body weight gain in obese db/db mice. Insulin and C-peptide levels, indicative of pancreatic function, were longer maintained in MGF-treated animals. MGF reduced central inflammation by lowering microglia burden, both in the cortex and the hippocampus. Likewise, central spontaneous bleeding was significantly reduced in db/db mice. Cortical and hippocampal atrophy was reduced in db/db mice and tau hyperphosphorylation was lower after MGF treatment, resulting in partial recovery of learning and memory disabilities. Altogether, the data suggested that MGF treatment may provide a useful tool to target different aspects of AD and VaD pathology, and could lead to more effective clinical therapies for the prevention of metabolic related central complications associated with AD and VaD.

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Section: Spontaneous Bleeding In Db/db Mice Is Reversed By Long-term supporting

confidence: 88%

Section: Introductionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Cresyl Violet and Prussian Blue Stainingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mango leaf extract improves central pathology and cognitive impairment in a type 2 diabetes mouse model

et al. 2016

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Glial cell alterations in diabetes-induced neurodegeneration

Llorián-Salvador,

Cabeza-Fernández,

Gomez-Sanchez

et al. 2024

Cell. Mol. Life Sci.

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Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if diabetes is primarily a metabolic disorder, it is now well established that key aspects of the pathogenesis of diabetes are associated with nervous system alterations, including deleterious chronic inflammation of neural tissues, referred here as neuroinflammation, along with different detrimental glial cell responses to stress conditions and neurodegenerative features. Moreover, diabetes resembles accelerated aging, further increasing the risk of developing age-linked neurodegenerative disorders. As such, the most common and disabling diabetic comorbidities, namely diabetic retinopathy, peripheral neuropathy, and cognitive decline, are intimately associated with neurodegeneration. As described in aging and other neurological disorders, glial cell alterations such as microglial, astrocyte, and Müller cell increased reactivity and dysfunctionality, myelin loss and Schwann cell alterations have been broadly described in diabetes in both human and animal models, where they are key contributors to chronic noxious inflammation of neural tissues within the PNS and CNS. In this review, we aim to describe in-depth the common and unique aspects underlying glial cell changes observed across the three main diabetic complications, with the goal of uncovering shared glial cells alterations and common pathological mechanisms that will enable the discovery of potential targets to limit neuroinflammation and prevent neurodegeneration in all three diabetic complications. Diabetes and its complications are already a public health concern due to its rapidly increasing incidence, and thus its health and economic impact. Hence, understanding the key role that glial cells play in the pathogenesis underlying peripheral neuropathy, retinopathy, and cognitive decline in diabetes will provide us with novel therapeutic approaches to tackle diabetic-associated neurodegeneration. Graphical abstract

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Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline

et al. 2023

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Aims/hypothesis Type 2 diabetes is associated with increased risk of cognitive decline although the pathogenic basis for this remains obscure. Deciphering diabetes-linked molecular mechanisms in cells of the cerebral cortex could uncover novel therapeutic targets. Methods Single-cell transcriptomic sequencing (scRNA-seq) was conducted on the cerebral cortex in a mouse model of type 2 diabetes (db/db mice) and in non-diabetic control mice in order to identify gene expression changes in distinct cell subpopulations and alterations in cell type composition. Immunohistochemistry and metabolic assessment were used to validate the findings from scRNA-seq and to investigate whether these cell-specific dysfunctions impact the neurovascular unit (NVU). Furthermore, the behavioural and cognitive alterations related to these dysfunctions in db/db mice were assessed via Morris water maze and novel object discrimination tests. Finally, results were validated in post-mortem sections and protein isolates from individuals with type 2 diabetes. Results Compared with non-diabetic control mice, the db/db mice demonstrated disrupted brain function as revealed by losses in episodic and spatial memory and this occurred concomitantly with dysfunctional NVU, neuronal circuitry and cerebral atrophy. scRNA-seq of db/db mouse cerebral cortex revealed cell population changes in neurons, glia and microglia linked to functional regulatory disruption including neuronal maturation and altered metabolism. These changes were validated through immunohistochemistry and protein expression analysis not just in the db/db mouse cerebral cortex but also in post-mortem sections and protein isolates from individuals with type 2 diabetes (74.3 ± 5.5 years) compared with non-diabetic control individuals (87.0 ± 8.5 years). Furthermore, metabolic and synaptic gene disruptions were evident in cortical NVU cell populations and associated with a decrease in vascular density. Conclusions/interpretation Taken together, our data reveal disruption in the cellular and molecular architecture of the cerebral cortex induced by diabetes, which can explain, at least in part, the basis for progressive cognitive decline in individuals with type 2 diabetes. Data availability The single-cell sequencing data that supports this study are available at GEO accession GSE217665 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE217665). Graphical Abstract

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Long-term central pathology and cognitive impairment are exacerbated in a mixed model of Alzheimer’s disease and type 2 diabetes

Cited by 52 publications

References 51 publications

Mango leaf extract improves central pathology and cognitive impairment in a type 2 diabetes mouse model

Mango leaf extract improves central pathology and cognitive impairment in a type 2 diabetes mouse model

Glial cell alterations in diabetes-induced neurodegeneration

Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline

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