Dysfunctional Glucose Metabolism in Alzheimer’s Disease Onset and Potential Pharmacological Interventions

Kim, Jaebong; Kim, So-Hyeon; Bishayee, Kausik

doi:10.3390/ijms23179540

Cited by 49 publications

(24 citation statements)

References 138 publications

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“…A number of postmortem studies have indicated that resistance to insulin and IGF-1, with the aberrant activation of their signaling pathway components, as well as reduced insulin/IGF-1 levels as neurotrophic factors, can be detected in the brains of AD patients [ 43 , 127 , 128 , 129 , 130 ], and these abnormalities are more severe in areas involved in cognitive performance, particularly in the hippocampus [ 131 ]. In fact, the early stages of AD, potentially decades before the development of symptoms, are characterized by deficits in cerebral carbohydrate metabolism that worsen with disease progression [ 40 , 132 , 133 ]. Likewise, insulin-resistant elderly people [ 26 , 134 ], T2D patients with mild cognitive impairment [ 135 , 136 ], and even prediabetic patients with normal cognitive function [ 49 , 134 ] show brain hypometabolism quantified by a decreased uptake of [ 18 F]-FDG (18-fluorodeoxyglucose) detected by PET (positron emission tomography) imaging.…”

Section: Molecular Mechanisms Linking T2d To Admentioning

confidence: 99%

“…Likewise, insulin-resistant elderly people [ 26 , 134 ], T2D patients with mild cognitive impairment [ 135 , 136 ], and even prediabetic patients with normal cognitive function [ 49 , 134 ] show brain hypometabolism quantified by a decreased uptake of [ 18 F]-FDG (18-fluorodeoxyglucose) detected by PET (positron emission tomography) imaging. Interestingly, the central impairment of glucose metabolism has been associated with insulin and IGF-1 resistance [ 40 , 132 , 133 , 137 ] and is mostly apparent in the frontal, parietotemporal, and cingulate cortices [ 134 ], indicating that insulin resistance affects the same regions as those affected by AD [ 54 ], and suggesting a link between central insulin resistance and this neurodegenerative disease.…”

Section: Molecular Mechanisms Linking T2d To Admentioning

confidence: 99%

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Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

Hamzé

Delangre

Tolu

et al. 2022

IJMS

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The global prevalence of diabetes mellitus and Alzheimer’s disease is increasing alarmingly with the aging of the population. Numerous epidemiological data suggest that there is a strong association between type 2 diabetes and an increased risk of dementia. These diseases are both degenerative and progressive and share common risk factors. The amyloid cascade plays a key role in the pathophysiology of Alzheimer’s disease. The accumulation of amyloid beta peptides gradually leads to the hyperphosphorylation of tau proteins, which then form neurofibrillary tangles, resulting in neurodegeneration and cerebral atrophy. In Alzheimer’s disease, apart from these processes, the alteration of glucose metabolism and insulin signaling in the brain seems to induce early neuronal loss and the impairment of synaptic plasticity, years before the clinical manifestation of the disease. The large amount of evidence on the existence of insulin resistance in the brain during Alzheimer’s disease has led to the description of this disease as “type 3 diabetes”. Available animal models have been valuable in the understanding of the relationships between type 2 diabetes and Alzheimer’s disease, but to date, the mechanistical links are poorly understood. In this non-exhaustive review, we describe the main molecular mechanisms that may link these two diseases, with an emphasis on impaired insulin and IGF-1 signaling. We also focus on GSK3β and DYRK1A, markers of Alzheimer’s disease, which are also closely associated with pancreatic β-cell dysfunction and type 2 diabetes, and thus may represent common therapeutic targets for both diseases.

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Section: Molecular Mechanisms Linking T2d To Admentioning

confidence: 99%

Section: Molecular Mechanisms Linking T2d To Admentioning

confidence: 99%

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

Hamzé

Delangre

Tolu

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Alzheimer's disease (AD) is clinically manifested as cognitive decline and memory impairment (Reitz and Mayeux, 2014;Liu et al, 2019). It is one of the leading causes of global mortality and the most common type of dementia worldwide (Chornenkyy et al, 2019;Kumar et al, 2022b). And the prevalence of AD has been increasing steadily over the past decades (Nichols et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…The major pathological characteristics of AD are beta-amyloid (Aβ) deposits and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein (Grundke-Iqbal et al, 1986;Selkoe and Schenk, 2003). However, a full understanding of the mechanism is still lacking (Kumar et al, 2022a;Kumar et al, 2022b). Currently, there are still no specific drugs, despite the increasing incidence of AD and the social problems it poses (Moran et al, 2019;Srivastava et al, 2021;Michailidis et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…DM could be responsible for the progression of not only peripheral nervous system diseases but central nervous system (CNS) diseases. Abnormal metabolism in the brain is regarded as one of the main features of AD, including impaired glucose metabolism (Jack et al, 2013;Kumar et al, 2022b;González et al, 2022) and the imbalance of energy metabolism (Akhtar et al, 2016;Carvalho and Cardoso, 2021;González et al, 2022). This may eventually lead to brain lesions through a series of impaired metabolic pathways (Kellar and Craft, 2020;Michailidis et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Hypoglycemic medicines in the treatment of Alzheimer’s disease: Pathophysiological links between AD and glucose metabolism

Wang

Liu

et al. 2023

Front. Pharmacol.

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Alzheimer’s Disease (AD) is a global chronic disease in adults with beta-amyloid (Aβ) deposits and hyperphosphorylated tau protein as the pathologic characteristics. Although the exact etiology of AD is still not fully elucidated, aberrant metabolism including insulin signaling and mitochondria dysfunction plays an important role in the development of AD. Binding to insulin receptor substrates, insulin can transport through the blood-brain barrier (BBB), thus mediating insulin signaling pathways to regulate physiological functions. Impaired insulin signaling pathways, including PI3K/Akt/GSK3β and MAPK pathways, could cause damage to the brain in the pathogenesis of AD. Mitochondrial dysfunction and overexpression of TXNIP could also be causative links between AD and DM. Some antidiabetic medicines may have benefits in the treatment of AD. Metformin can be beneficial for cognition improvement in AD patients, although results from clinical trials were inconsistent. Exendin-4 may affect AD in animal models but there is a lack of clinical trials. Liraglutide and dulaglutide could also benefit AD patients in adequate clinical studies but not semaglutide. Dipeptidyl peptidase IV inhibitors (DPP4is) such as saxagliptin, vildagliptin, linagliptin, and sitagliptin could boost cognitive function in animal models. And SGLT2 inhibitors such as empagliflozin and dapagliflozin were also considerably protective against new-onset dementia in T2DM patients. Insulin therapy is a promising therapy but some studies indicated that it may increase the risk of AD. Herbal medicines are helpful for cognitive function and neuroprotection in the brain. For example, polyphenols, alkaloids, glycosides, and flavonoids have protective benefits in cognition function and glucose metabolism. Focusing on glucose metabolism, we summarized the pharmacological mechanism of hypoglycemic drugs and herbal medicines. New treatment approaches including antidiabetic synthesized drugs and herbal medicines would be provided to patients with AD. More clinical trials are needed to produce definite evidence for the effectiveness of hypoglycemic medications.

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Reconstructing Molecular Networks by Causal Diffusion Do‐Calculus Analysis with Deep Learning

Wang,

Zhang,

Chen

et al. 2024

Advanced Science

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Quantifying molecular regulations between genes/molecules causally from observed data is crucial for elucidating the molecular mechanisms underlying biological processes at the network level. Presently, most methods for inferring gene regulatory and biological networks rely on association studies or observational causal‐analysis approaches. This study introduces a novel approach that combines intervention operations and diffusion models within a do‐calculus framework by deep learning, i.e., Causal Diffusion Do‐calculus (CDD) analysis, to infer causal networks between molecules. CDD can extract causal relations from observed data owing to its intervention operations, thereby significantly enhancing the accuracy and generalizability of causal network inference. Computationally, CDD has been applied to both simulated data and real omics data, which demonstrates that CDD outperforms existing methods in accurately inferring gene regulatory networks and identifying causal links from genes to disease phenotypes. Especially, compared with the Mendelian randomization algorithm and other existing methods, the CDD can reliably identify the disease genes or molecules for complex diseases with better performances. In addition, the causal analysis between various diseases and the potential factors in different populations from the UK Biobank database is also conducted, which further validated the effectiveness of CDD.

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Dysfunctional Glucose Metabolism in Alzheimer’s Disease Onset and Potential Pharmacological Interventions

Cited by 49 publications

References 138 publications

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

Hypoglycemic medicines in the treatment of Alzheimer’s disease: Pathophysiological links between AD and glucose metabolism

Reconstructing Molecular Networks by Causal Diffusion Do‐Calculus Analysis with Deep Learning

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