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Journal ArticleDOI

Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal.

TL;DR: Significant shared mechanisms between AD and diabetes are discussed and therapeutic avenues for diabetes and AD are provided and the effects of insulin in the pathology of AD through cellular and molecular mechanisms are provided.
About: This article is published in Biochimica et Biophysica Acta.The article was published on 2017-05-01 and is currently open access. It has received 376 citations till now. The article focuses on the topics: Insulin resistance & Insulin.
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Journal ArticleDOI
TL;DR: The role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease are discussed.
Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.

967 citations


Cites background from "Is Alzheimer's disease a Type 3 Dia..."

  • ...Alzheimer’s disease (AD) affects more than 5 million Americans, with numbers expected to grow as the population ages [1, 2]....

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Journal ArticleDOI
TL;DR: A particular role in melatonin's actions seems to be associated with the upregulation of sirtuin‐1 (SIRT1), which shares various effects known from melatonin and additionally interferes with the signaling by the mechanistic target of rapamycin and Notch, and reduces the expression of the proinflammatory lncRNA‐CCL2.
Abstract: Melatonin is an immune modulator that displays both pro- and anti-inflammatory properties. Proinflammatory actions, which are well documented by many studies in isolated cells or leukocyte-derived cell lines, can be assumed to enhance the resistance against pathogens. However, they can be detrimental in autoimmune diseases. Anti-inflammatory actions are of particular medicinal interest, because they are observed in high-grade inflammation such as sepsis, ischemia/reperfusion, and brain injury, and also in low-grade inflammation during aging and in neurodegenerative diseases. The mechanisms contributing to anti-inflammatory effects are manifold and comprise various pathways of secondary signaling. These include numerous antioxidant effects, downregulation of inducible and inhibition of neuronal NO synthases, downregulation of cyclooxygenase-2, inhibition of high-mobility group box-1 signaling and toll-like receptor-4 activation, prevention of inflammasome NLRP3 activation, inhibition of NF-κB activation and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). These effects are also reflected by downregulation of proinflammatory and upregulation of anti-inflammatory cytokines. Proinflammatory actions of amyloid-β peptides are reduced by enhancing α-secretase and inhibition of β- and γ-secretases. A particular role in melatonin's actions seems to be associated with the upregulation of sirtuin-1 (SIRT1), which shares various effects known from melatonin and additionally interferes with the signaling by the mechanistic target of rapamycin (mTOR) and Notch, and reduces the expression of the proinflammatory lncRNA-CCL2. The conclusion on a partial mediation by SIRT1 is supported by repeatedly observed inhibitions of melatonin effects by sirtuin inhibitors or knockdown.

264 citations

Journal ArticleDOI
TL;DR: The many causes of obesity are described, including key roles that a dysbiotic intestinal microbiome plays in metabolic derangements accompanying obesity, increased calorie absorption, and increased appetite and fat storage.

254 citations


Cites background from "Is Alzheimer's disease a Type 3 Dia..."

  • ...Finally, Alzheimer disease is strongly associated with chronic insulin resistance (36)....

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Journal ArticleDOI
TL;DR: This review will present an overview of the current understanding of O-GlcNAc's regulation, functions, and roles in chronic diseases of aging.

235 citations

Journal ArticleDOI
TL;DR: The present review provides an insight to the different molecular mechanisms involved in the development and progression of the AD and potential therapeutic strategies, enlightening perceptions into structural information of conventional and novel targets along with the successful applications of computational approaches for the design of target-specific inhibitors.

194 citations

References
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Journal ArticleDOI
19 Mar 1999-Cell
TL;DR: It is demonstrated that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors, which triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.

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17 Oct 1997-Cell
TL;DR: It is shown that growth factor activation of the PI3'K/Akt signaling pathway culminates in the phosphorylation of the BCL-2 family member BAD, thereby suppressing apoptosis and promoting cell survival.

5,831 citations


"Is Alzheimer's disease a Type 3 Dia..." refers background in this paper

  • ...The key molecule for the neuroprotective function of IGF/insulin signaling is PKB (Akt) which may be mediated by direct phosphorylation of known regulators of apoptosis, such as the proapoptoticmitochondrial protein Bad [51,52] and the transcription factor FOXO [53–55], as well as the pro-survival transcription factors CREB [56] and NF-kB [57,58]....

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  • ...A critical appraisal☆ Ramesh Kandimalla a,⁎, Vani Thirumala a,b, P. Hemachandra Reddy a,c a Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, United States b BSA Neuroscience, University of Texas at Austin, Austin, TX 78712, USA c Departments of Cell Biology & Biochemistry, Neuroscience & Pharmacology and Neurology, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, United States Abbreviations: AD, Alzheimer's disease; BBB, blood br Advanced Glycation End products; AGE, advanced g interleukin 1 beta; Aβ, amyloid beta; TNF∝, tumor transforming growth factor beta; ApoE4, apolipoprote precursor protein; Aβ, β-amyloid; T2DM, type 2 diabetes kappa-light-chain-enhancer of activated B; GSK3β, Gl NMDAR, N-methyl-D-aspartate receptor; AMPAR, α-a isoxazolepropionic acid receptor; Bax, Bcl2 associated X protein; Bcl2, B-cell leukemia/lymphoma2; Drp1, dynamin loid-beta-derived diffusible ligands; AβOs, β-amyloid amyloid polypeptide; IR, insulin receptor; IRS, insulin r phatidylinositol 3-kinase; PIP2, phosphatidylinositol 4 phatidylinositol 3,4,5 trisphosphate; PKB, protein kinase GABA, gamma amino butyric acid; PSD-95, post synaptic d ease; ROS, reactive oxygen species; RNS, reactive nitrogen ed protein kinase; SOD, superoxide dismutase; GSH-Px catalase; Bad, Bcl2 associated death promoter; FOXO, Fork ing transcription factor 4; eIF2a, eukaryotic translation cerebro ventricular; IGF-1, insulin-like growth factor 1; LTP, long term potentiation; PERK, PKR-like endoplasmic stranded RNA-dependent protein kinase; CREB, cAMP-res PS1, presenilins 1; PS2, presenilins 2; BIM, Bcl like prote trophic factor; IDE, insulin degrading enzyme; STZ, stre proliferator-activated receptors; VDAC1, voltage depende ☆ This article is part of a Special Issue entitled: Oxida Quality in Diabetes/Obesity and Critical Illness Spec P. Hemachandra Reddy....

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  • ...apoptoticmitochondrial protein Bad [51,52] and the transcription factor FOXO [53–55], as well as the pro-survival transcription factors CREB...

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Journal ArticleDOI
TL;DR: It is hypothesized that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways.
Abstract: Aβ1–42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer’s pathogenesis. Neurotoxicity of amyloid β protein (Aβ) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible Aβ oligomers (referred to as ADDLs, for Aβ-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer’s disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer’s disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Aβ-derived diffusible ligands acting upon particular neural signal transduction pathways.

3,608 citations

Journal ArticleDOI
24 Oct 1997-Science
TL;DR: The proapoptotic function of BAD is regulated by the PI 3-kinase-Akt pathway, and active, but not inactive, forms of Akt were found to phosphorylate BAD in vivo and in vitro at the same residues that are phosphorylated in response to IL-3.
Abstract: BAD is a distant member of the Bcl-2 family that promotes cell death. Phosphorylation of BAD prevents this. BAD phosphorylation induced by interleukin-3 (IL-3) was inhibited by specific inhibitors of phosphoinositide 3-kinase (PI 3-kinase). Akt, a survival-promoting serine-threonine protein kinase, was activated by IL-3 in a PI 3-kinase-dependent manner. Active, but not inactive, forms of Akt were found to phosphorylate BAD in vivo and in vitro at the same residues that are phosphorylated in response to IL-3. Thus, the proapoptotic function of BAD is regulated by the PI 3-kinase-Akt pathway.

2,321 citations

Journal ArticleDOI
TL;DR: This review is focused on the 3-phosphoinositide lipids, the synthesis of which is acutely triggered by extracellular stimuli, the enzymes responsible for their synthesis and metabolism, and their cell biological roles.
Abstract: The 3-phosphorylated inositol lipids fulfill roles as second messengers by interacting with the lipid binding domains of a variety of cellular proteins. Such interactions can affect the subcellular localization and aggregation of target proteins, and through allosteric effects, their activity. Generation of 3-phosphoinositides has been documented to influence diverse cellular pathways and hence alter a spectrum of fundamental cellular activities. This review is focused on the 3-phosphoinositide lipids, the synthesis of which is acutely triggered by extracellular stimuli, the enzymes responsible for their synthesis and metabolism, and their cell biological roles. Much knowledge has recently been gained through structural insights into the lipid kinases, their interaction with inhibitors, and the way their 3-phosphoinositide products interact with protein targets. This field is now moving toward a genetic dissection of 3-phosphoinositide action in a variety of model organisms. Such approaches will reveal the true role of the 3-phosphoinositides at the organismal level in health and disease.

1,630 citations

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