scholarly journals Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yanan Sun ◽  
Cao Ma ◽  
Hui Sun ◽  
Huan Wang ◽  
Wei Peng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Metabolic Disease ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Diabetic Patients ◽  
Increased Risk ◽  
Impaired Insulin ◽  
The Brain

As a chronic metabolic disease, diabetes mellitus (DM) is broadly characterized by elevated levels of blood glucose. Novel epidemiological studies demonstrate that some diabetic patients have an increased risk of developing dementia compared with healthy individuals. Alzheimer’s disease (AD) is the most frequent cause of dementia and leads to major progressive deficits in memory and cognitive function. Multiple studies have identified an increased risk for AD in some diabetic populations, but it is still unclear which diabetic patients will develop dementia and which biological characteristics can predict cognitive decline. Although few mechanistic metabolic studies have shown clear pathophysiological links between DM and AD, there are several plausible ways this may occur. Since AD has many characteristics in common with impaired insulin signaling pathways, AD can be regarded as a metabolic disease. We conclude from the published literature that the body’s diabetic status under certain circumstances such as metabolic abnormalities can increase the incidence of AD by affecting glucose transport to the brain and reducing glucose metabolism. Furthermore, due to its plentiful lipid content and high energy requirement, the brain’s metabolism places great demands on mitochondria. Thus, the brain may be more susceptible to oxidative damage than the rest of the body. Emerging evidence suggests that both oxidative stress and mitochondrial dysfunction are related to amyloid-β (Aβ) pathology. Protein changes in the unfolded protein response or endoplasmic reticulum stress can regulate Aβ production and are closely associated with tau protein pathology. Altogether, metabolic disorders including glucose/lipid metabolism, oxidative stress, mitochondrial dysfunction, and protein changes caused by DM are associated with an impaired insulin signal pathway. These metabolic factors could increase the prevalence of AD in diabetic patients via the promotion of Aβ pathology.

Mitochondrial Dysfunction as a Causative Factor in Alzheimer’s Disease-Spectrum Disorders: Lymphocytes as a Window to the Brain

2021 ◽  
Vol 18 ◽  
Author(s):  
Marko Jörg ◽  
Johanna E. Plehn ◽  
Kristina Friedland ◽  
Walter E. Müller
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Late Onset ◽  
Causative Factor ◽  
Disease Spectrum ◽  
The Brain ◽  
Peripheral Markers

: Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will further increase with longer life expectancy. The AD brain is marked by severe neurodegeneration, such as the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems, especially in the hip- pocampus and cerebral cortex. Recent findings highlight the important role of mitochondrial dys- function and increased oxidative stress in the pathophysiology of late-onset Alzheimer’s disease (LOAD). These alterations are not only observed in the brain of AD patients but also in the periph- ery. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and mitochondrial dysfunction as peripheral markers for the detection of AD in blood cells e.g. lymphocytes. We evaluate recent findings regarding impaired mitochondrial function comprising mitochondrial respiration, reduced complex activities of the respiratory chain and altered Mitochon- drial Membrane Potential (MMP) in lymphocytes as well as in neurons. Finally, we will question whether these mitochondrial parameters might be suitable as an early peripheral marker for the de- tection of LOAD but also for the transitional stage between normal aging and Dementia, “Mild Cognitive Impairment” (MCI).

Molecular and Biochemical Pathways Encompassing Diabetes Mellitus and Dementia

2021 ◽  
Vol 20 ◽  
Author(s):  
Tapan Behl ◽  
Arpita Arora ◽  
Aayush Sehgal ◽  
Sukhbir Singh ◽  
Neelam Sharma ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Vicious Cycle ◽  
Early Therapy ◽  
Impaired Insulin ◽  
The Brain

: Diabetes mellitus is a major metabolic disorder that has now emerged as an epidemic, and it affects the brain through an array of pathways. Diabetes mellitus patients can develop pathological changes in the brain, which eventually take the shape of mild cognitive impairment progressing to Alzheimer’s Disease. A number of preclinical and clinical studies demonstrate this fact, and it comes out to be those molecular pathways such as amyloidogenesis, oxidative stress, inflammation, and impaired insulin signaling are identical in diabetes mellitus and dementia. However, the critical player involved in the vicious cycle of diabetes mellitus and dementia is insulin, whose signaling, when impaired in diabetes mellitus (both type 1 and 2), leads to a decline in cognition, although other pathways are also essential contributors. Moreover, it is not only that diabetes mellitus patients indicate cognitive decline at a later stage; many Alzheimer’s Disease patients also reflect symptoms of diabetes mellitus, thus creating a vicious cycle inculcating a web of complex molecular mechanisms and hence categorizing Alzheimer’s Disease as ‘brain diabetes’. Thus, it is practical to suggest that anti-diabetic drugs are beneficial in Alzheimer’s Disease; but only smaller trials, not the larger ones, have showcased positive outcomes mainly because of the late onset of therapy. Therefore, it is extremely important to develop more of such molecules that target insulin in dementia patients along with such methods that diagnose impaired insulin signaling and the associated cognitive decline so that early therapy may be initiated and the progression of the disease be prevented.

scholarly journals Potential of Sorghum Polyphenols to Prevent and Treat Alzheimer’s Disease: A Review Article

2021 ◽  
Vol 13 ◽  
Author(s):  
Nasim Rezaee ◽  
W.M.A.D. Binosha Fernando ◽  
Eugene Hone ◽  
Hamid R. Sohrabi ◽  
Stuart K. Johnson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Stress Reduction ◽  
Neuronal Damage ◽  
Tau Proteins ◽  
Farm Animals ◽  
Learning Impairments ◽  
The Brain

Alzheimer’s disease (AD) is characterized by the excessive deposition of extracellular amyloid-beta peptide (Aβ) and the build-up of intracellular neurofibrillary tangles containing hyperphosphorylated tau proteins. This leads to neuronal damage, cell death and consequently results in memory and learning impairments leading to dementia. Although the exact cause of AD is not yet clear, numerous studies indicate that oxidative stress, inflammation, and mitochondrial dysfunction significantly contribute to its onset and progression. There is no effective therapeutic approach to stop the progression of AD and its associated symptoms. Thus, early intervention, preferably, pre-clinically when the brain is not significantly affected, is a better option for effective treatment. Natural polyphenols (PP) target multiple AD-related pathways such as protecting the brain from Aβ and tau neurotoxicity, ameliorating oxidative damage and mitochondrial dysfunction. Among natural products, the cereal crop sorghum has some unique features. It is one of the major global grain crops but in the developed world, it is primarily used as feed for farm animals. A broad range of PP, including phenolic acids, flavonoids, and condensed tannins are present in sorghum grain including some classes such as proanthocyanidins that are rarely found in others plants. Pigmented varieties of sorghum have the highest polyphenolic content and antioxidant activity which potentially makes their consumption beneficial for human health through different pathways such as oxidative stress reduction and thus the prevention and treatment of neurodegenerative diseases. This review summarizes the potential of sorghum PP to beneficially affect the neuropathology of AD.

scholarly journals Shared Blood Transcriptomic Signatures between Alzheimer’s Disease and Diabetes Mellitus

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 34
Author(s):  
Taesic Lee ◽  
Hyunju Lee
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Interactions ◽  
Expression Patterns ◽  
Protein Protein Interactions ◽  
Hub Genes ◽  
Gene Modules ◽  
Gene Regulatory ◽  
The Brain

Alzheimer’s disease (AD) and diabetes mellitus (DM) are known to have a shared molecular mechanism. We aimed to identify shared blood transcriptomic signatures between AD and DM. Blood expression datasets for each disease were combined and a co-expression network was used to construct modules consisting of genes with similar expression patterns. For each module, a gene regulatory network based on gene expression and protein-protein interactions was established to identify hub genes. We selected one module, where COPS4, PSMA6, GTF2B, GTF2F2, and SSB were identified as dysregulated transcription factors that were common between AD and DM. These five genes were also differentially co-expressed in disease-related tissues, such as the brain in AD and the pancreas in DM. Our study identified gene modules that were dysregulated in both AD and DM blood samples, which may contribute to reveal common pathophysiology between two diseases.

scholarly journals Failure of the Brain Glucagon-Like Peptide-1-Mediated Control of Intestinal Redox Homeostasis in a Rat Model of Sporadic Alzheimer’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1118
Author(s):  
Jan Homolak ◽  
Ana Babic Perhoc ◽  
Ana Knezovic ◽  
Jelena Osmanovic Barilar ◽  
Melita Salkovic-Petrisic
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rat Model ◽  
Redox Homeostasis ◽  
Brain State ◽  
Gastrointestinal Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Brain

The gastrointestinal system may be involved in the etiopathogenesis of the insulin-resistant brain state (IRBS) and Alzheimer’s disease (AD). Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is being explored as a potential therapy as activation of brain GLP-1 receptors (GLP-1R) exerts neuroprotection and controls peripheral metabolism. Intracerebroventricular administration of streptozotocin (STZ-icv) is used to model IRBS and GLP-1 dyshomeostasis seems to be involved in the development of neuropathological changes. The aim was to explore (i) gastrointestinal homeostasis in the STZ-icv model (ii) assess whether the brain GLP-1 is involved in the regulation of gastrointestinal redox homeostasis and (iii) analyze whether brain-gut GLP-1 axis is functional in the STZ-icv animals. Acute intracerebroventricular treatment with exendin-3(9-39)amide was used for pharmacological inhibition of brain GLP-1R in the control and STZ-icv rats, and oxidative stress was assessed in plasma, duodenum and ileum. Acute inhibition of brain GLP-1R increased plasma oxidative stress. TBARS were increased, and low molecular weight thiols (LMWT), protein sulfhydryls (SH), and superoxide dismutase (SOD) were decreased in the duodenum, but not in the ileum of the controls. In the STZ-icv, TBARS and CAT were increased, LMWT and SH were decreased at baseline, and no further increment of oxidative stress was observed upon central GLP-1R inhibition. The presented results indicate that (i) oxidative stress is increased in the duodenum of the STZ-icv rat model of AD, (ii) brain GLP-1R signaling is involved in systemic redox regulation, (iii) brain-gut GLP-1 axis regulates duodenal, but not ileal redox homeostasis, and iv) brain-gut GLP-1 axis is dysfunctional in the STZ-icv model.

scholarly journals Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Amit U. Joshi ◽  
Lauren D. Van Wassenhove ◽  
Kelsey R. Logas ◽  
Paras S. Minhas ◽  
Katrin I. Andreasson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alcohol Consumption ◽  
Mitochondrial Dysfunction ◽  
Aldehyde Dehydrogenase ◽  
Cortical Neurons ◽  
Aldehyde Dehydrogenase 2 ◽  
East Asians

AbstractAldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

scholarly journals Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

2019 ◽  
Vol 12 (2) ◽  
pp. 93 ◽  
Author(s):  
Shashank Masaldan ◽  
Abdel Ali Belaidi ◽  
Scott Ayton ◽  
Ashley I. Bush
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hydroxyl Radicals ◽  
Iron Accumulation ◽  
Brain Iron ◽  
Dependent Cell ◽  
Cellular Dysfunction ◽  
The Impact ◽  
The Brain

Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.

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

2019 ◽  
Vol 9 (10) ◽  
pp. 262 ◽  
Author(s):  
Hayden
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Late Onset ◽  
Neurovascular Unit ◽  
Age Related ◽  
Increased Risk

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 and metabolic factors, which increase the cellular vulnerability to develop an increased risk of age-related 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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