Adenosine A<sub>2A</sub>Receptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway

Canas, Paula M.; Porciúncula, Lisiane O.; Cunha, G. M. A.; Silva, Carla G.; Machado, Nuno J.; Oliveira, Jorge M. A.; Oliveira, Catarina R.; Cunha, Rodrigo A.

doi:10.1523/jneurosci.3728-09.2009

Cited by 304 publications

(254 citation statements)

References 77 publications

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“…Interestingly, we failed to identify diabetes-induced neuronal loss in brain sections stained either cresyl violet or FluoroJade-C, which was corroborated by the lack of altered microtubuleassociated protein 2 (MAP2) immunoreactivity, a marker of neuronal density [95]. This indicates that T2D primarily causes synaptic deterioration without neuronal death, which resembles the events occurring in aging [128] and models mimicking early AD [129,130], thus corroborating the association of insulin resistance and T2D with increased incidence of AD. Moreover, compared to non-diabetic Wistar rats, also non-obese insulin-resistant Goto-Kakizyki (GK) rats displayed reduced spatial memory, which was accompanied by reduced pre-synaptic markers and increased glial specific proteins in the hippocampus [131].…”

Section: Insulin-resistant Diabetesmentioning

confidence: 58%

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

Duarte¹

2014

aging dis

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From epidemiological studies it is known that diabetes patients display increased risk of developing dementia. Moreover, cognitive impairment and Alzheimer's disease (AD) are also accompanied by impaired glucose homeostasis and insulin signalling. Although there is plenty of evidence for a connection between insulin-resistant diabetes and AD, definitive linking mechanisms remain elusive. Cerebrovascular complications of diabetes, alterations in glucose homeostasis and insulin signalling, as well as recurrent hypoglycaemia are the factors that most likely affect brain function and structure. While difficult to study in patients, the mechanisms by which diabetes leads to brain dysfunction have been investigated in experimental models that display phenotypes of the disease. The present article reviews the impact of diabetes and AD on brain structure and function, and discusses recent findings from translational studies in animal models that link insulin resistance to metabolic alterations that underlie brain dysfunction. Such modifications of brain metabolism are likely to occur at early stages of neurodegeneration and impact regional neurochemical profiles and constitute non-invasive biomarkers detectable by magnetic resonance spectroscopy (MRS).Key words: Neurodegeneration, Diabetes, Alzheimer's disease, Insulin, Metabolism Diabetes mellitus can be defined as a chronic metabolic disorder characterized by hyperglycaemia, resulting from inappropriate insulin secretion and/or action [1]. The vast majority of the diabetes cases are included in two main categories, classified according to the underlying cause, which are type 1 diabetes (T1D) or insulindependent diabetes, generally caused by an autoimmune reaction to antigens of pancreatic β-cells, leading to impaired insulin production, and type 2 diabetes (T2D) or insulin-resistant diabetes, characterised by inefficiency of insulin action. While T1D is mainly observed in children and adolescents, T2D is more common among adults, accounting for more than 90% of the diabetes cases worldwide. The prevalence of diabetes and impaired glucose tolerance achieved now epidemic proportions, respectively at 6.9% and 8.3% of the world population, and predicted to raise to 8. 0% and 10.1% in 2035 [2]. Moreover, diabetes is nowadays a leading cause of death accounting for 8.4% of global mortality in people aged between 20 and 79 years [2]. The main contributor for the high prevalence of diabetes is the rise of obesity, related to the combination of ample food availability and a sedentary lifestyle, contrasting to less abundant food supplies and higher physical activity observed until a century ago.Diabetes is associated with the occurrence of well described microvascular complications that affect different organs, leading most commonly to retinopathy, nephropathy and peripheral neuropathy, which development is dependent on the duration of the disease and glycaemia control [3]. When the control of the disorder allowed patients to live longer and without these Volume 6, N...

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Section: Insulin-resistant Diabetesmentioning

confidence: 58%

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

Duarte¹

2014

aging dis

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“…On the one hand, A 2A R inactivation can protect the brain against various insults including ischemia, excitotoxicity, and mitochondrial toxicity (Cunha, 2005). For example, genetic and pharmacological inactivation of A 2A Rs downregulates neuroinflammation and protects brain tissue against ischemia (Phillis, 1995;Chen et al, 1999), the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and 6-OHDA (6-hydroxydopamine) (Chen et al, 2001;Ikeda et al, 2002;Yu et al, 2008), excitotoxicity (Jones et al, 1998a,b;Popoli et al, 2002), ␤-amyloid aggregation (Dall'Igna et al, 2007;Canas et al, 2009), and traumatic brain injury (TBI) (Li et al, 2009). The protective effect of A 2A R inactivation in the brain has been attributed to inhibition of glutamate release and suppression of proinflammatory cytokines (Popoli et al, 1995Yu et al, 2004;Cunha, 2005;Chen et al, 2007;Stone and Behan, 2007).…”

Section: Introductionmentioning

confidence: 99%

Local Glutamate Level Dictates Adenosine A_2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

Dai¹,

Zhou²,

Li³

et al. 2010

J. Neurosci.

144

120

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“…The blockade of A 2A receptors has recently been demonstrated to limit the synaptotoxic effect of amyloid-β (Aβ), a peptide that accumulates in the brain of AD patients [5]. Experimental studies conducted in animal models have also shown that adenosine A 2A and metabotropic glutamate 5 receptors are co-located and that the former play a permissive role in mGlu5R receptor-mediated potentiation of NMDA effects in the hippocampus [6].…”

Section: Introductionmentioning

confidence: 99%

Caffeine Intake is Associated with a Lower Risk of Cognitive Decline: A Cohort Study from Portugal

Santos

Lunet

Azevedo

et al. 2010

JAD

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Abstract. Alzheimer's disease has emerged in recent decades as a major health problem and the role of lifestyles in the modulation of risk has been increasingly recognized. Recent epidemiological studies suggest a protective effect for caffeine intake in dementia. We aimed to quantify the association between caffeine dietary intake and cognitive decline, in a cohort of adults living in Porto. A cohort of 648 subjects aged 65 years was recruited between 1999 . Follow-up evaluation (2005-2008 was carried out on 58.2% of the eligible participants and 10.9% were deceased. Caffeine exposure in the year preceding baseline evaluation was assessed with a validated food frequency questionnaire. Cognitive evaluation consisted of baseline and follow-up Mini-Mental State Examination (MMSE). Cognitive decline was defined by a decrease 2 points in the MMSE score between evaluations. Relative risk (RR) and 95% confidence interval (95%CI) estimates adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes were computed using Poisson regression. Caffeine intake (> 62 mg/day [3rd third] vs. < 22 mg/day [1st third]) was associated with a lower risk of cognitive decline in women (RR = 0.49, 95%CI 0.24-0.97), but not significantly in men (RR = 0.65, 95%CI 0.27-1.54). Our study confirms the negative association between caffeine and cognitive decline in women.

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Adenosine A_2AReceptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway

Cited by 304 publications

References 77 publications

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

Local Glutamate Level Dictates Adenosine A_2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

Caffeine Intake is Associated with a Lower Risk of Cognitive Decline: A Cohort Study from Portugal

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Adenosine A2AReceptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway

Cited by 304 publications

References 77 publications

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

Local Glutamate Level Dictates Adenosine A2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

Caffeine Intake is Associated with a Lower Risk of Cognitive Decline: A Cohort Study from Portugal

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Product

Resources

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Adenosine A_2AReceptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway

Local Glutamate Level Dictates Adenosine A_2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury