scholarly journals Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence?

2016 ◽  
Vol 213 (8) ◽  
pp. 1375-1385 ◽  
Author(s):  
Molly Stanley ◽  
Shannon L. Macauley ◽  
David M. Holtzman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Insulin Signaling ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Intranasal Insulin ◽  
Increased Risk ◽  
High Insulin ◽  
Neuronal Insulin Resistance

Individuals with type 2 diabetes have an increased risk for developing Alzheimer’s disease (AD), although the causal relationship remains poorly understood. Alterations in insulin signaling (IS) are reported in the AD brain. Moreover, oligomers/fibrils of amyloid-β (Aβ) can lead to neuronal insulin resistance and intranasal insulin is being explored as a potential therapy for AD. Conversely, elevated insulin levels (ins) are found in AD patients and high insulin has been reported to increase Aβ levels and tau phosphorylation, which could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a cause or consequence of AD.

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.

scholarly journals Type 2 Diabetes Mellitus and Alzheimer’s Disease: Role of Insulin Signalling and Therapeutic Implications

2018 ◽  
Vol 19 (11) ◽  
pp. 3306 ◽  
Author(s):  
Andrea Tumminia ◽  
Federica Vinciguerra ◽  
Miriam Parisi ◽  
Lucia Frittitta
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Cell Activation ◽  
Insulin Signalling ◽  
Amyloid Β ◽  
Neuronal Stem Cell

In the last two decades, numerous in vitro studies demonstrated that insulin receptors and theirs downstream pathways are widely distributed throughout the brain. This evidence has proven that; at variance with previous believes; insulin/insulin-like-growth-factor (IGF) signalling plays a crucial role in the regulation of different central nervous system (CNS) tasks. The most important of these functions include: synaptic formation; neuronal plasticity; learning; memory; neuronal stem cell activation; neurite growth and repair. Therefore; dysfunction at different levels of insulin signalling and metabolism can contribute to the development of a number of brain disorders. Growing evidences demonstrate a close relationship between Type 2 Diabetes Mellitus (T2DM) and neurodegenerative disorders such as Alzheimer’s disease. They, in fact, share many pathophysiological characteristics comprising impaired insulin sensitivity, amyloid β accumulation, tau hyper-phosphorylation, brain vasculopathy, inflammation and oxidative stress. In this article, we will review the clinical and experimental evidences linking insulin resistance, T2DM and neurodegeneration, with the objective to specifically focus on insulin signalling-related mechanisms. We will also evaluate the pharmacological strategies targeting T2DM as potential therapeutic tools in patients with cognitive impairment.

A-19 The Effect of Type 2 Diabetes on Attention and Executive Functioning in Mild Cognitive Impairment Patients

2021 ◽  
Vol 36 (6) ◽  
pp. 1060-1060
Author(s):  
Zachary Peart ◽  
Samantha Spagna ◽  
Bailey McDonald ◽  
Brittny Arias ◽  
D'anna Sydow ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Executive Functioning ◽  
Digit Span ◽  
Research Centers ◽  
Disease Research ◽  
Altered Glucose ◽  
Increased Risk

Abstract Objective To investigate the effects of Type 2 Diabetes (T2D) on performance on attention and executive function measures in a sample of MCI patients. Method Individuals with a clinician diagnosis of MCI with T2D and [n = 719,Mage = 75.24,50.3% female] and MCI persons without T2D [n = 719,Mage = 75.21,47.1% female] were selected from the Alzheimer’s Disease Research Centers database by the National Institute on Aging. Those with motor disturbances were excluded from the analysis. Significant differences (p < 0.001) were found for race and education between groups. Results Multiple ANCOVAs controlled for gender, education, age, and race on performance. Significant differences (p < 0.001) were found in performance on the Trail Making Test [A, B], Digit Span forward [longest recall, correct trials], Digit Span backward [longest recall, correct trials], and Verbal Fluency tasks [F word, L words]. No significant differences were found in the animal and vegetable naming fluency tasks. The T2D group showed poorer mean scores on every test analyzed. Conclusion Results indicated modestly lower performance on measures of attention and executive functioning in MCI patients with comorbid T2D. Previous research supports these conclusions, as T2D has been associated with increased risk for dementia, accelerated decline from MCI to dementia, and modestly lower scores on cognitive tests via effects of microvascular function and altered glucose metabolism. Future studies should aim to identify protective factors in T2D cognitive decrements while controlling for exercise, diet, SES, and underlying medical comorbidities. The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded Alzheimer’s Disease Research Centers.

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.

Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease

2014 ◽  
Vol 35 (12) ◽  
pp. 2883.e3-2883.e10 ◽  
Author(s):  
Petroula Proitsi ◽  
Michelle K. Lupton ◽  
Latha Velayudhan ◽  
Gillian Hunter ◽  
Stephen Newhouse ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Increased Risk ◽  
Increase Risk

scholarly journals Investigating the role of APOE: limitations of human pluripotent stem cell-derived cerebral organoids

2020 ◽  
Author(s):  
Damián Hernández ◽  
Louise A. Rooney ◽  
Maciej Daniszewski ◽  
Lerna Gulluyan ◽  
Helena H. Liang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Line ◽  
Human Fibroblasts ◽  
Susceptibility Gene ◽  
Tau Phosphorylation ◽  
Isogenic Lines ◽  
Apoe Ε4 ◽  
Increased Risk ◽  
Β Amyloid

SummaryApolipoprotein E (APOE) is the most important susceptibility gene for late onset of Alzheimer’s disease, with the presence of APOE-ε4 associated with increased risk of developing Alzheimer’s disease. Here, we reprogrammed human fibroblasts from individuals with different APOE-ε genotypes into induced pluripotent stem cells, and generated isogenic lines with different APOE profiles. We then differentiated these into cerebral organoids for six months and assessed the suitability of this in vitro system to measure APOE, β amyloid, and Tau phosphorylation levels. We identified intra- and inter-variabilities in the organoids’ cell composition. Using the CRISPR-edited APOE isogenic lines, we observed more homogenous cerebral organoids, and similar levels of APOE, β amyloid, and Tau between the isogenic lines, with the exception of one site of Tau phosphorylation which was higher in the APOE-ε4/ε4 organoids. These data describe that pathological hallmarks of AD are observed in cerebral organoids, and that their variation is mainly independent of the APOE-ε status of the cells, but associated with the high variability of cerebral organoid differentiation. It demonstrates that the batch-to-batch and cell-line-to-cell-line variabilities need to be considered when using cerebral organoids.

scholarly journals Alzheimer’s-like pathology in aging rhesus macaques: Unique opportunity to study the etiology and treatment of Alzheimer’s disease

2019 ◽  
Vol 116 (52) ◽  
pp. 26230-26238 ◽  
Author(s):  
Amy F. T. Arnsten ◽  
Dibyadeep Datta ◽  
Shannon Leslie ◽  
Sheng-Tao Yang ◽  
Min Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Immunoelectron Microscopy ◽  
Rhesus Monkeys ◽  
Early Stage ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Association Cortex ◽  
Tau Pathology

Although mouse models of Alzheimer’s disease (AD) have provided tremendous breakthroughs, the etiology of later onset AD remains unknown. In particular, tau pathology in the association cortex is poorly replicated in mouse models. Aging rhesus monkeys naturally develop cognitive deficits, amyloid plaques, and the same qualitative pattern and sequence of tau pathology as humans, with tangles in the oldest animals. Thus, aging rhesus monkeys can play a key role in AD research. For example, aging monkeys can help reveal how synapses in the prefrontal association cortex are uniquely regulated compared to the primary sensory cortex in ways that render them vulnerable to calcium dysregulation and tau phosphorylation, resulting in the selective localization of tau pathology observed in AD. The ability to assay early tau phosphorylation states and perform high-quality immunoelectron microscopy in monkeys is a great advantage, as one can capture early-stage degeneration as it naturally occurs in situ. Our immunoelectron microscopy studies show that phosphorylated tau can induce an “endosomal traffic jam” that drives amyloid precursor protein cleavage to amyloid-β in endosomes. As amyloid-β increases tau phosphorylation, this creates a vicious cycle where varied precipitating factors all lead to a similar phenotype. These data may help explain why circuits with aggressive tau pathology (e.g., entorhinal cortex) may degenerate prior to producing significant amyloid pathology. Aging monkeys therefore can play an important role in identifying and testing potential therapeutics to protect the association cortex, including preventive therapies that are challenging to test in humans.

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