scholarly journals Diabetes and Alzheimer’s Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1257
Author(s):  
Maria Assunta Potenza ◽  
Luca Sgarra ◽  
Vanessa Desantis ◽  
Carmela Nacci ◽  
Monica Montagnani
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Senile Plaques ◽  
Mitochondrial Activity ◽  
Enhanced Production ◽  
The Common ◽  
The Brain

A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer’s disease (AD). Indeed, the proposed definition of Alzheimer’s disease as type 3 diabetes (T3D) underlines the key role played by deranged insulin signaling to accumulation of aggregated amyloid beta (Aβ) peptides in the senile plaques of the brain. Metabolic disturbances such as hyperglycemia, peripheral hyperinsulinemia, dysregulated lipid metabolism, and chronic inflammation associated with T2DM are responsible for an inefficient transport of insulin to the brain, producing a neuronal insulin resistance that triggers an enhanced production and deposition of Aβ and concomitantly contributes to impairment in the micro-tubule-associated protein Tau, leading to neural degeneration and cognitive decline. Furthermore, the reduced antioxidant capacity observed in T2DM patients, together with the impairment of cerebral glucose metabolism and the decreased performance of mitochondrial activity, suggests the existence of a relationship between oxidative damage, mitochondrial impairment, and cognitive dysfunction that could further reinforce the common pathophysiology of T2DM and AD. In this review, we discuss the molecular mechanisms by which insulin-signaling dysregulation in T2DM can contribute to the pathogenesis and progression of AD, deepening the analysis of complex mechanisms involved in reactive oxygen species (ROS) production under oxidative stress and their possible influence in AD and T2DM. In addition, the role of current therapies as tools for prevention or treatment of damage induced by oxidative stress in T2DM and AD will be debated.

scholarly journals The Role of Irisin in Alzheimer’s Disease

2018 ◽  
Vol 7 (11) ◽  
pp. 407 ◽  
Author(s):  
Oh Kim ◽  
Juhyun Song
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Background ◽  
Senile Plaques ◽  
Metabolic Dysfunction ◽  
Lipid Imbalance ◽  
The Relationship ◽  
The Brain

Alzheimer’s disease (AD) is characterized by progressive memory dysfunction, oxidative stress, and presence of senile plaques formed by amyloid beta (A β ) accumulation in the brain. AD is one of the most important causes of morbidity and mortality worldwide. AD has a variety of risk factors, including environmental factors, metabolic dysfunction, and genetic background. Recent research has highlighted the relationship between AD and systemic metabolic changes such as glucose and lipid imbalance and insulin resistance. Irisin, a myokine closely linked to exercise, has been associated with glucose metabolism, insulin sensitivity, and fat browning. Recent studies have suggested that irisin is involved in the process in central nervous system (CNS) such as neurogenesis and has reported the effects of irisin on AD as one of the neurodegenerative disease. Here, we review the roles of irisin with respect to AD and suggest that irisin highlight therapeutic important roles in AD. Thus, we propose that irisin could be a potential future target for ameliorating AD pathology and preventing AD onset.

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.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

scholarly journals High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

2021 ◽  
Vol 22 (7) ◽  
pp. 3746
Author(s):  
Ilaria Zuliani ◽  
Chiara Lanzillotta ◽  
Antonella Tramutola ◽  
Eugenio Barone ◽  
Marzia Perluigi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
High Fat Diet ◽  
Mitochondrial Activity ◽  
High Fat ◽  
Hexosamine Biosynthetic Pathway ◽  
Neurodegenerative Process ◽  
The Brain

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.

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 Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cells ◽  
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.

Fractal Dimension of the EEG in Alzheimer's Disease

2008 ◽  
pp. 603-609 ◽  
Author(s):  
Daniel Abásolo ◽  
Javier Escudero ◽  
Roberto Hornero ◽  
Pedro Espino ◽  
Carlos Gómez
Keyword(s):  
Magnetic Resonance Imaging ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Differential Diagnosis ◽  
Senile Plaques ◽  
Cortical Atrophy ◽  
Definite Diagnosis ◽  
Histological Changes ◽  
Brain Scans ◽  
The Brain

Alzheimer’s disease (AD) is the most frequent cause of dementia in western countries, and is characterized by progressive impairments in cognition and memory, whose course lasts several years prior to death (Jeong, 2004). These clinical features are accompanied by histological changes in the brain, which include widespread cortical atrophy, intracellular deposition of neurofibrillary tangles, and extracellular deposition of senile plaques, particularly in the hippocampus and the cerebral cortex. Although a definite diagnosis is only possible by necropsy, a differential diagnosis with other types of dementia and with major depression should be attempted. Magnetic resonance imaging and computerized tomography can be normal in the early stages of AD, but a diffuse cortical atrophy is the main sign in brain scans. Mental status tests are also useful.

scholarly journals Modulating Effect of Diet on Alzheimer’s Disease

Diseases ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 12 ◽  
Author(s):  
Paloma Fernández-Sanz ◽  
Daniel Ruiz-Gabarre ◽  
Vega García-Escudero
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Response ◽  
Scientific Evidence ◽  
Senile Plaques ◽  
Neuronal Loss ◽  
Pleiotropic Effect ◽  
Amyloid Peptide ◽  
Dietary Recommendations

As life expectancy is growing, neurodegenerative disorders, such as Alzheimer’s disease, are increasing. This disease is characterised by the accumulation of intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein, senile plaques composed of an extracellular deposit of β-amyloid peptide (Aβ), and neuronal loss. This is accompanied by deficient mitochondrial function, increased oxidative stress, altered inflammatory response, and autophagy process impairment. The present study gathers scientific evidence that demonstrates that specific nutrients exert a direct effect on both Aβ production and Tau processing and their elimination by autophagy activation. Likewise, certain nutrients can modulate the inflammatory response and the oxidative stress related to the disease. However, the extent to which these effects come with beneficial clinical outcomes remains unclear. Even so, several studies have shown the benefits of the Mediterranean diet on Alzheimer’s disease, due to its richness in many of these compounds, to which can be attributed their neuroprotective properties due to the pleiotropic effect they show on the aforementioned processes. These indications highlight the potential role of adequate dietary recommendations for clinical management of both Alzheimer’s diagnosed patients and those in risk of developing it, emphasising once again the importance of diet on health.

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