Age‐dependent impairment of glucose tolerance in the 3xTg‐AD mouse model of Alzheimer's disease

Vandal, Milène; White, Phillip J.; Chevrier, Geneviève; Tremblay, Cyntia; St‐Amour, Isabelle; Planel, Emmanuel; Marette, André; Calon, Frédéric

doi:10.1096/fj.14-268482

Cited by 97 publications

(109 citation statements)

References 82 publications

(121 reference statements)

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“…1C). Taken together, these data suggest peripheral glucose insulin resistance in 16-month-old 3xTg-AD mice; this finding is consistent with previous reports (Vandal et al, 2015). …”

Section: Resultssupporting

confidence: 93%

“…Specifically, phosphorylated IRS recruits the heterodimeric p85/p110 PI3K at the plasma membrane, where it produces the second messenger phosphatidylinositol-4,5-bisphosphate 3- (PIP3) kinase, which in turn activates a serine/threonine phosphorylation cascade of PH-domain containing proteins (Alessi and Downes, 1998). PIP3 targets include PDK1, the serine/threonine protein kinase B (PKB)/Akt, and the atypical protein kinases C ζ and λ isoforms (Dineley et al, 2014; Vandal et al, 2015). GSK-3β, a convergent target of the PDK1/AKT pathways, induces glycogen synthesis through the target of rapamycin complexes to control AMP-activated protein kinase (AMPK), energy metabolism, mitochondrial function, synaptic plasticity and memory (Cheng et al, 2010; Kleinridders et al, 2014; Stoica et al, 2011; White, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…These changes are accompanied by peripheral insulin resistance by 9 months of age (as measured by the GTT), which coincides with the onset of Aβ accumulation in the brain (Hsiao et al, 1996; Pedersen and Flynn, 2004; Rodriguez-Rivera et al, 2011). Further, 14-month-old female 3xTg-AD mice develop insulin resistance, fasting hyperinsulinemia and hyperglycemia (Vandal et al, 2015). The link between insulin resistance and AD is further strengthened by data showing that diet-induced insulin resistance exacerbates Aβ accumulation, tau phosphorylation and cognitive impairments, and leads to the development of a diabetes-like phenotype (Cao et al, 2007; Carvalho et al, 2012; Orr et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease

Velázquez

Tran

Ishimwe

et al. 2017

Neurobiology of Aging

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Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide. While the causes of AD are not known, several risk factors have been identified. Among these, type 2 diabetes (T2D), a chronic metabolic disease, is one of the most prevalent risk factors for AD. Insulin resistance, which is associated with T2D, is defined as diminished or absent insulin signaling, and is reflected by peripheral blood hyperglycemia and impaired glucose clearance. In this study, we used complimentary approaches to probe for peripheral insulin resistance, central nervous system (CNS) insulin sensitivity and energy homeostasis in Tg2576 and 3xTg-AD mice, two widely used animal models of AD. We report that CNS insulin signaling abnormalities are evident months before peripheral insulin resistance. Additionally, we find that brain energy metabolism is differentially altered in both mouse models, with the 3xTg-AD mice showing more extensive changes. Collectively, our data suggest that early AD may reflect engagement of different signaling networks that influence CNS metabolism, which in-turn may alter peripheral insulin signaling.

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“…1C). Taken together, these data suggest peripheral glucose insulin resistance in 16-month-old 3xTg-AD mice; this finding is consistent with previous reports (Vandal et al, 2015). …”

Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease

Velázquez

Tran

Ishimwe

et al. 2017

Neurobiology of Aging

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show abstract

“…This finding indicates that the prion promoter itself may be a useful tool for driving robust gene expression of target genes specifically within the endocrine compartment of the pancreas. It has recently been reported that a 3xTg-AD model of Alzheimer’s disease, which uses Thy 1.2 promoter, also overexpresses human APP within pancreatic islets (Vandal et al 2015). Because of the similarity in gene expression and phenotype between pancreatic islets and neurons, it is likely that numerous genetic elements which drive high expression of genes in the central nervous system will also result in robust islet gene expression (Atouf, et al 1997; Martens, et al 2011; Moller, et al 1992).…”

Section: Discussionmentioning

confidence: 99%

“…There are conflicting reports of the detection of amyloid beta within human islets (Miklossy, et al 2010; Oskarsson, et al 2015). Increased levels of Aβ or Aβ aggregates have been detected within the pancreas of some transgenic mouse models of AD (Shoji, et al 1998; Shoji, et al 2000; Vandal, et al 2015; Wegiel, et al 2000). …”

Section: Introductionmentioning

confidence: 99%

Amyloid precursor protein in pancreatic islets

Kulas

Puig

Combs

2017

Journal of Endocrinology

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The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Aβ), a plaque forming peptide in Alzheimer’s disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well characterized consequence of type 1 and type 2 diabetes. In this study we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes. Our data demonstrates the presence of APP within the pancreas, including pancreatic islets in both mouse and human samples. Additionally, we report that the APP/PS1 mouse model of AD overexpresses APP within pancreatic islets, although this did not result in detectable levels of Aβ. We compared whole pancreas and islet culture lysates by western blot from C57BL/6 (WT), APP−/−, and APP/PS1 mice and observed APP-dependent differences in the total protein levels of GLUT4, IDE and BACE2. Immunohistochemistry for BACE2 detected high levels in pancreatic α cells. Additionally, both mouse and human islets processed APP to release sAPP into cell culture media. Moreover, sAPP stimulated insulin but not glucagon secretion from islet cultures. We conclude that APP and its metabolites are capable of influencing the basic physiology of the pancreas, possibly through the release of sAPP acting in an autocrine or paracrine manner.

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Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

Jash

Gondaliya

Kirave

et al. 2019

Drug Development Research

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Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting millions of people worldwide. Diabetes is associated with various complications like nephropathy, neuropathy, retinopathy, diabetic foot, cognitive impairment, and many more. Evidence suggests that cognitive dysfunction is a rising complication of diabetes which adversely affects the brain of patients suffering from diabetes. Age‐related memory impairment is a complication having its major effect on people suffering from diabetes and Alzheimer's. Patients suffering from diabetes are at two times higher risk of developing cognitive dysfunction as compared with normal individuals. Multiple factors which are involved in diabetes related complications are found to play a role in the development of neurodegeneration in Alzheimer's. The problem of insulin deficiency and insulin resistance is well reported in diabetes but there are many studies which suggest dysregulation of insulin levels as a reason behind the development of Alzheimer's. As the link between diabetes and Alzheimer disease (AD) is deepening, there is a need to understand the plausible tie‐ins between the two. Emerging role of major factors like insulin imbalance, advanced glycation end products and micro‐RNA's involved in diabetes and Alzheimer's have been discussed here. This review helps in understanding the plausible mechanism underlying the pathophysiology of amyloid beta (Aβ) plaque formation and tau hyperphosphorylation as well provides information about studies carried out in this area of research. The final thought is to enhance the scientific knowledge on this correlation and develop future therapeutics to treat the same.

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Age‐dependent impairment of glucose tolerance in the 3xTg‐AD mouse model of Alzheimer's disease

Cited by 97 publications

References 82 publications

Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease

Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease

Amyloid precursor protein in pancreatic islets

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

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