Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease

Mullins, Roger J.; Diehl, Thomas C.; Chia, Chee W.; Kapogiannis, Dimitrios

doi:10.3389/fnagi.2017.00118

Cited by 120 publications

(83 citation statements)

References 219 publications

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“…It is well established that tau protein is regulated by insulin and IGF signaling and insulin signaling dysregulation often results in tau (de la Monte, 2012; Himmelstein et al, 2012; Ke et al, 2009; Yarchoan et al, 2014). Thus, it is likely that the more robust changes in insulin signaling in older 3xTg-AD mice leads to tau hyperphosphorylation, possibly through altered function of tau kinases and phosphatases (de la Monte, 2012; Ke et al, 2009; Mairet-Coello et al, 2013; Mullins et al, 2017; Vingtdeux et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Regarding the role of the NLRP3-in ammasome in linking systemic in ammaging to functional decline in aging [5], our ndings highlight TXNIP's role in age-associated dementia. Data from tandem mass analysis [60] and functional human brain imaging are producing intriguing knowledge of a spatial correlation between AD pathology and genes implicated in glucose metabolism [61]. This supports the hypothesis that enhanced TXNIP transcription may perturb brain metabolism, stimulate NLRP3-in ammasome and contribute to senile dementia as exempli ed in AD.…”

Section: Discussionmentioning

confidence: 60%

TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

Ismael¹,

Nasoohi²,

Yoo³

et al. 2020

Preprint

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Background Immune system hypersensitivity with aging is believed to contribute to mental frailty in elderlies. This is postulated to arise from accumulation of oxidative molecular patterns. Solid evidences delineates thioredoxin interacting protein (TXNIP), an inducible protein involved in oxidative stress, is essential for NOD-like receptor pyrin domain containing-3 (NLRP3)-inflammasome activation which intimately connects “inflammaging” to senile cognitive decline. This study aims to fundamentally explore the plausible involvement of TXNIP/NLRP3 inflammasome pathway in senile dementia and the typical Alzhemier’s disease. Methods In experimental studies cerebral samples from gender-matched mice were compared for TXNIP/NLRP3 inflammasome activation and klotho depletion, through immunoblotting and immunostaining in different life span points. In aged males, genetic or pharmacological ablation of TXNIP were then used to determine effects on cognitive decline and sensorimotor frailty in morris water maze, novel object recognition test and gait control analysis. Immunoblotting/staining experiments were also performed on human postmortem aged hippocampal specimens and 5XFAD transgenic mice, to ultimately address Alzheimer’s disease (AD) as the most age related dementia. Results According to our preclinical studies, cerebral TXNIP was significantly upregulated in aged animals, paralleled by the NLRP3-inflammasome over-activity in both sexes, and closely associated klotho depletion in aged males. TXNIP knock-out reversed age-related NLRP3-hyperactivity and enhanced thioredoxin (TRX) levels in aged brains. Further, pharmacological TXNIP inhibition replicated the TXNIP/NLRP3-inflammasome downregulation in aged animals, with FOXO-1 and mTOR upregulation. These alterations concurred with substantial improvements in both cognitive and sensorimotor abilities. Moreover, our immunostaining shows a significant increase of TXNIP in transgenic 5XFAD mice brain and TXNIP/NLRP3-inflammasome activity in AD human postmortem hippocampal specimens, in proximity of p-tau tangles and β-amyloid plaques. Conclusion Together, these findings substantiate the pivotal role of TXNIP to drive inflammging in parallel with klotho depletion and functional decline. TXNIP co-localization with hallmarks of AD pathology is further supportive of potential mechanistic links between TXNIP and AD. Unraveling new information on upstream pathways, these data support modulating thioredoxin system as a potential approach to decelerate senile frailty.

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“…For each 1-point decrement on a 10-point memory scale there was a 14.5% increased risk of depression two years later [34]. These bidirectional relations may be due to a shared common pathogenic pathway that includes insulin resistance, persistent hyperglycaemia, repeated episodes of hypoglycaemia, mitochondrial dysfunction, oxidative stress, advanced glycation end products, reduced cerebral amyloid clearance, diabetes-related complications and vascular disease [35,36].…”

Section: Diabetes-cognition-mood Interactionmentioning

confidence: 99%

Management of Older People With Diabetes - A Focus On Mental Functions

Abdelhafiz¹

2020

OBM Geriatrics

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The prevalence of diabetes in older people is increasing. Diabetes in old age is associated with increased risk of mental dysfunction. Cognitive dysfunction and mood disorders such as depression, anxiety and diabetes-related distress tend to coexist in older people with diabetes and appear to have bidirectional relationship acting as a risk factor and, at the same time, as a consequence of diabetes. To break the vicious circle of this complex reciprocal relationship between diabetes and mental dysfunction, early identification and treatment is important. Healthy lifestyle, appropriate glycaemic control, hypoglycaemia risk reduction and an organised and a holistic care is appropriate. Therefore, health care professionals involved in the care of older people with diabetes should be aware of this associated mental dysfunction and a collaborative care approach that includes integrated care of both physical and mental health is required.

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Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease

Cited by 120 publications

References 219 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

TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

Management of Older People With Diabetes - A Focus On Mental Functions

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