Alzheimer’s disease and insulin resistance: translating basic science into clinical applications

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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Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cells ◽

10.3390/cells10051236 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1236

Author(s):

Jesús Burillo ◽

Patricia Marqués ◽

Beatriz Jiménez ◽

Carlos González-Blanco ◽

Manuel Benito ◽

...

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Alzheimer's Disease ◽

Type 2 Diabetes Mellitus ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

Progressive Disease

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

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From obesity to Alzheimer's disease through insulin resistance

Journal of Diabetes and its Complications ◽

10.1016/j.jdiacomp.2021.108026 ◽

2021 ◽

Vol 35 (11) ◽

pp. 108026 ◽

Cited By ~ 1

Author(s):

Simona Terzo ◽

Antonella Amato ◽

Flavia Mulè

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease

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Stress contributes to the development of central insulin resistance during aging: Implications for Alzheimer’s disease

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2013.09.013 ◽

2013 ◽

Vol 1832 (12) ◽

pp. 2332-2339 ◽

Cited By ~ 26

Author(s):

Maite Solas ◽

Bárbara Aisa ◽

Rosa M. Tordera ◽

María C. Mugueta ◽

María J. Ramírez

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease

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Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

Molecules ◽

10.3390/molecules24101992 ◽

2019 ◽

Vol 24 (10) ◽

pp. 1992 ◽

Cited By ~ 10

Author(s):

Firas H. Bazzari ◽

Dalaal M. Abdallah ◽

Hanan S. El-Abhar

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Chenodeoxycholic Acid ◽

Insulin Signaling ◽

Glucose Transporter ◽

Farnesoid X Receptor ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Significant Difference

Insulin resistance is a major risk factor for Alzheimer’s disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (Aβ42). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl3-treated rats, which highlights its potential in AD management.

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P2-107: Brain Insulin Resistance and Alzheimer's Disease Neuropathology Among Older Autopsied Persons With and Without Diabetes

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.1313 ◽

2016 ◽

Vol 12 ◽

pp. P653-P653

Author(s):

Rexford S. Ahima ◽

Ana W. Capuano ◽

Julie A. Schneider ◽

David A. Bennett ◽

Steven E. Arnold ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Brain Insulin ◽

Brain Insulin Resistance

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Moderating Effect of Insulin Resistance on the Relationship between Gray Matter Volumes and Cognitive Function

Journal of Clinical Medicine ◽

10.3390/jcm7110413 ◽

2018 ◽

Vol 7 (11) ◽

pp. 413 ◽

Cited By ~ 2

Author(s):

Jiyeon Lee ◽

Jihyeon Kim ◽

Seong Shin ◽

Soowon Park ◽

Dong Yoon ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Cognitive Decline ◽

Gray Matter ◽

Structural Changes ◽

Gray Matter Volume ◽

Volume Loss ◽

Matter Volume

Background: It is controversial whether exposure to insulin resistance accelerates cognitive deterioration. The present study aimed to investigate the association between insulin resistance and gray matter volume loss to predict the cognitive decline. Methods: We recruited 160 participants (78 with Alzheimer’s disease and 82 without Alzheimer’s disease). Insulin resistance, regional gray matter volume, and cognitive function were assessed. A hierarchical moderated multiple regression (MMR) model was used to determine any associations among insulin resistance, structural changes in the brain, and cognitive decline. Results: The volumes of 7 regions in the gray matter were negatively related to insulin resistance in Alzheimer’s disease (p =0.032). Hierarchical MMR analysis indicated that insulin resistance did not directly affect the cognitive decline but moderated the cognitive decline through the decrease in gray matter volume in the key brain regions, i.e., inferior orbitofrontal gyrus (left), middle cingulate gyrus (right), hippocampus (right), and precuneus (right) (p < 0.05 in each case). Conclusion: Insulin resistance appears to exacerbate the cognitive decline associated with several gray matter volume loss.

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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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Fleshing out the amyloid cascade hypothesis: the molecular biology of Alzheimer's disease

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2000.2.2/slovestone ◽

2000 ◽

Vol 2 (2) ◽

pp. 101-110 ◽

Cited By ~ 1

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Biology ◽

Basic Science ◽

Amyloid Protein ◽

Amyloid Cascade Hypothesis ◽

Protein Tau ◽

Disease Modifying Therapies ◽

Disease Modifying ◽

Amyloid Cascade

Alzheimer's disease (AD) is a disorder of two pathologies- plaques and tangles. The former have as a key constituent amyloid protein and the latter the microtubule-associaied protein tau. Genetics has demonstrated that changes in either protein are sufficient to cause dementia. The amyloid cascade hypothesis proposes that plaque-related changes precede tangle-related changes and positions amyloid as central to the degeneration of AD. All the evidence suggests this is correct, including evidence that presenil ins alter the processing of the amyloid precursor protein and evidence that disrupting the normal properties of tau underlies the related froniotemporal dementias. The amyloid cascade hypothesis has provided the basis for nearly a decade of intensive basic science - the skeleton of that hypothesis can now be fleshed out, and confidence is growing that this will result in useful disease-modifying therapies in the future.

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Pathology, Risk Factors, and Oxidative Damage Related to Type 2 Diabetes-Mediated Alzheimer’s Disease and the Rescuing Effects of the Potent Antioxidant Anthocyanin

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/4051207 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Muhammad Sohail Khan ◽

Muhammad Ikram ◽

Tae Ju Park ◽

Myeong Ok Kim

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Alzheimer's Disease ◽

Inflammatory Cytokines ◽

Amyloid Beta ◽

Acid Oxidation ◽

Chronic Hyperglycemia ◽

Underlying Mechanisms

The pathology and neurodegeneration in type 2 diabetes- (T2D-) mediated Alzheimer’s disease (AD) have been reported in several studies. Despite the lack of information regarding the basic underlying mechanisms involved in the development of T2D-mediated AD, some common features of the two conditions have been reported, such as brain atrophy, reduced cerebral glucose metabolism, and insulin resistance. T2D phenotypes such as glucose dyshomeostasis, insulin resistance, impaired insulin signaling, and systemic inflammatory cytokines have been shown to be involved in the progression of AD pathology by increasing amyloid-beta accumulation, tau hyperphosphorylation, and overall neuroinflammation. Similarly, oxidative stress, mitochondrial dysfunction, and the generation of advanced glycation end products (AGEs) and their receptor (RAGE) as a result of chronic hyperglycemia may serve as critical links between diabetes and AD. The natural dietary polyflavonoid anthocyanin enhances insulin sensitivity, attenuates insulin resistance at the level of the target tissues, inhibits free fatty acid oxidation, and abrogates the release of peripheral inflammatory cytokines in obese (prediabetic) individuals, which are responsible for insulin resistance, systemic hyperglycemia, systemic inflammation, brain metabolism dyshomeostasis, amyloid-beta accumulation, and neuroinflammatory responses. In this review, we have shown that obesity may induce T2D-mediated AD and assessed the recent therapeutic advances, especially the use of anthocyanin, against T2D-mediated AD pathology. Taken together, the findings of current studies may help elucidate a new approach for the prevention and treatment of T2D-mediated AD by using the polyflavonoid anthocyanin.

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