Dementia, Diabetes, Alzheimer's Disease, and Insulin Resistance in the Brain: Progress, Dilemmas, New Opportunities, and a Hypothesis to Tackle Intersecting Epidemics

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.

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The Role of Long Noncoding RNAs in Diabetic Alzheimer’s Disease

Journal of Clinical Medicine ◽

10.3390/jcm7110461 ◽

2018 ◽

Vol 7 (11) ◽

pp. 461 ◽

Cited By ~ 4

Author(s):

Young-Kook Kim ◽

Juhyun Song

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Glucose Dysregulation ◽

Near Future ◽

The Brain

Long noncoding RNAs (lncRNAs) are involved in diverse physiological and pathological processes by modulating gene expression. They have been found to be dysregulated in the brain and cerebrospinal fluid of patients with neurodegenerative diseases, and are considered promising therapeutic targets for treatment. Among the various neurodegenerative diseases, diabetic Alzheimer’s disease (AD) has been recently emerging as an important issue due to several unexpected reports suggesting that metabolic issues in the brain, such as insulin resistance and glucose dysregulation, could be important risk factors for AD. To facilitate understanding of the role of lncRNAs in this field, here we review recent studies on lncRNAs in AD and diabetes, and summarize them with different categories associated with the pathogenesis of the diseases including neurogenesis, synaptic dysfunction, amyloid beta accumulation, neuroinflammation, insulin resistance, and glucose dysregulation. It is essential to understand the role of lncRNAs in the pathogenesis of diabetic AD from various perspectives for therapeutic utilization of lncRNAs in the near future.

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Insulin resistance in the brain: A new therapeutic target for Alzheimer's disease

Journal of Diabetes Investigation ◽

10.1111/jdi.12027 ◽

2013 ◽

Vol 4 (2) ◽

pp. 150-151 ◽

Cited By ~ 8

Author(s):

Hiroyuki Umegaki

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Therapeutic Target ◽

The Brain

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The relationship of diabetes mellitus with Alzheimer’s disease: a literature review

10.5327/1516-3180.280 ◽

2021 ◽

Author(s):

Fábio Dias Nogueira ◽

Ana Klara Rodrigues Alves ◽

Barbara Beatriz Lira da Silva ◽

Ana Kamila Rodrigues Alves ◽

Marlilia Moura Coelho Sousa ◽

...

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Glycogen Synthase ◽

Potential Link ◽

The Central Nervous System ◽

Gsk 3Β ◽

Type 3 ◽

The Brain

Introduction: Alzheimer’s disease (AD) is closely related to diabetes mellitus (DM), and AD is also considered to be type 3 diabetes (T3D). Glycogen synthase kinase-3β (GSK-3β) may be the potential link between DM and AD. GSK-3β is one of the main factors that lead to insulin deficiency and insulin resistance, and insulin resistance is a characteristic of the development of DM. In AD, GSK-3β plays an important role in hyperphosphorylation of the tau protein (tau) associated with microtubules, which is one of the pathological features in AD. Objective: To analyze DM as a factor for the development of AD. METHODOLOGY: This is an integrative review of the literature, which is a construction of a comprehensive analysis of the literature with pre-defined steps, carried out through PubMed, 1.501 articles were found, of which 10 were selected, through the simultaneous crossing between the descriptors “Diabetes mellitus”, “Alzheimer “. Articles written in Portuguese and English published between 2016 and 2021 were inserted. Results: DM associated with insulin resistance affects psychomotor efficiency, attention, learning memory, mental flexibility, speed and executive function of the brain, thus being an independent risk factor for cognitive impairment and damage to the central nervous system, hyperglycemia, which can cause increased oxidative stress leading to progressive functional and structural abnormalities in the brain. Conclusion:The risk of dementia in patients with DM is higher than in nondiabetic patients and it is also well known that DM2 / insulin resistance is involved in AD.

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Mechanisms of Brain Aging Regulation by Insulin: Implications for Neurodegeneration in Late-Onset Alzheimer's Disease

ISRN Neurology ◽

10.5402/2011/306905 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 21

Author(s):

Artur F. Schuh ◽

Carlos M. Rieder ◽

Liara Rizzi ◽

Márcia Chaves ◽

Matheus Roriz-Cruz

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Brain Aging ◽

Late Onset ◽

Energy Deficit ◽

Insulin Degrading Enzyme ◽

Microvascular Endothelium ◽

Chronic Hyperglycemia ◽

The Brain

Insulin and IGF seem to be important players in modulating brain aging. Neurons share more similarities with islet cells than any other human cell type. Insulin and insulin receptors are diffusely found in the brain, especially so in the hippocampus. Caloric restriction decreases insulin resistance, and it is the only proven mechanism to expand lifespan. Conversely, insulin resistance increases with age, obesity, and sedentarism, all of which have been shown to be risk factors for late-onset Alzheimer's disease (AD). Hyperphagia and obesity potentiate the production of oxidative reactive species (ROS), and chronic hyperglycemia accelerates the formation of advanced glucose end products (AGEs) in (pre)diabetes—both mechanisms favoring a neurodegenerative milieu. Prolonged high cerebral insulin concentrations cause microvascular endothelium proliferation, chronic hypoperfusion, and energy deficit, triggering β-amyloid oligomerization and tau hyperphosphorylation. Insulin-degrading enzyme (IDE) seems to be the main mechanism in clearing β-amyloid from the brain. Hyperinsulinemic states may deviate IDE utilization towards insulin processing, decreasing β-amyloid degradation.

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The role of metabolic syndrome in Alzheimer’s disease

10.5327/1516-3180.319 ◽

2021 ◽

Author(s):

Gláucia Maria Senhorinha ◽

Arlys Emanuel Mendes da Silva Santos ◽

Douglas Daniel Dophine

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Metabolic Syndrome ◽

Brain Regions ◽

Alzheimer Dementia ◽

The Metabolic Syndrome ◽

The Brain

Background: Metabolic syndrome (MS) leads to the deposits formation of insoluble protein aggregates, neuroinflammation, oxidative stress, neuronal insulin resistance, progressive insulin resistance, desensitization and β-amyloid amyloidosis in the brain, besides direct ischemic effects which are closely associated with Alzheimer’s disease (AD).1 Objectives: The present study seeks to understand the role of the metabolic syndrome in the pathophysiology of Alzheimer’s disease and to describe preventive and therapeutic interventions. Methods: PUBMED and Web of Science were the databases used, the following descriptors were used to search the articles: “Alzheimer Disease” OR “Alzheimer Dementia” AND “Metabolic Syndrome”. Results: The studies in general have shown that MS is related to AD through brain insulin resistance, triggered by oxidative stress and neuroinflammation. It is related to the progressive atrophy of brain regions involved in the progression of AD. Insulin resistance in the brain is related to the progressive atrophy of the brain regions from initial progression of AD. These regions are cingulate cortices, medial temporal lobe, prefrontal gyri and other regions.³ Thus, there is an inhibition of the mechanisms of beta-amyloid removal, leading to its accumulation, which generates neuroinflammation, that in turn potentiates insulin resistance in the central nervous system, contributing to the genesis and progression of cognitive damage.2,3 Conclusions: Insulin resistance plays a major role in the initiation and perpetuation of cognitive impairment in AD. Furthermore, the components of the MS associated with AD, when treated with preventive and therapeutic measures, break this association by promoting rebalancing of the metabolism.

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Trimethylamine N-Oxide (TMAO) links peripheral insulin resistance and cognitive deficiencies in a senescence accelerated mouse model

10.1101/2021.11.17.469001 ◽

2021 ◽

Author(s):

Manuel H. Janeiro ◽

Elena Puerta ◽

Maria Lanz ◽

Fermin I. Milagro ◽

Maria J Ramirez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Insulin Signaling ◽

Samp8 Mouse ◽

Cognitive Deficiencies ◽

Samp8 Mice ◽

The Brain ◽

Senescence Accelerated Mouse

It has been established that ageing is the major risk factor for cognitive deficiency or neurodegenerative diseases such as Alzheimer's disease (AD) and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. The dysfunction of the insulin signaling system and glucose metabolism has been proposed to be responsible for brain aging. Normal insulin signaling in the brain is required to mediate growth, metabolic functions, and the survival of neurons and glia. Insulin receptors are densely expressed in the olfactory bulb, the cerebral cortex and the hippocampus and regulate neurotransmitter release and receptor recruitment. In normal elderly individuals, reduced glucose tolerance and decreased insulin levels in the aged brain are typically observed. Furthermore, insulin signaling is aberrantly activated in the AD brain, leading to non-responsive insulin receptor signaling. The senescence accelerated mouse (SAMP8) mouse was one of the accelerated senescence strains that spontaneously developed from breeding pairs of the AKR/J series. The SAMP8 mouse develops early learning and memory deficits (between 6 and 8 months) together with other characteristics similar to those seen in Alzheimer's disease. The present project proposes the investigation of the missing link between aging, insulin resistance and dementia. Peripheral but not central insulin resistance was found in SAMP8 mice accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state (i.e. significantly higher adipose tissue TNF-[alpha]; and IL6 levels) were observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across a aging-disrupted BBB. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment inhibits the transformation of choline, carnitine and crotonobetaine, decreaseing TMAO levels. The ever-increasing incidence of neurodegenerative diseases not only limits the life quality of the affected individuals and their families but also poses an enormous demand on the societies. Thus, it is instrumental to pursue novel promising approaches to prevent and treat it at the highest possible speed to rapidly translate them to clinical practice. From this point of view, data obtained from this project will be instrumental to validate the principle approach of microbial dysbiosis and increased TMAO secretion as a key link between aging, insulin resistance and dementia. Collectively, the proposed experiments ideally integrate the aim to promote a novel approach to improve the lives of those suffering from cognitive disturbances.

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