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Link Between Type 2 Diabetes and Alzheimer's Disease Journal name: Drug Design, Development and Therapy Article Designation: Review Year: 2018 Volume: 12 Drug Design, Development and Therapy Dovepress Running head verso: Rad et al Running head recto: Molecular links between type 2 diabetes and Alzheimer’s disease open access to scientific and medical research DOI: 173970 Open Access Full Text Article REVIEW Mechanism involved in insulin resistance via accumulation of β-amyloid and neurofibrillary tangles: link between type 2 diabetes and Alzheimer’s disease Sima Kianpour Rad1 Abstract: The pathophysiological link between type 2 diabetes mellitus (T2DM) and Aditya Arya2–4 Alzheimer’s disease (AD) has been suggested in several reports. Few findings suggest that Hamed Karimian2 T2DM has strong link in the development process of AD, and the complete mechanism is yet Priya Madhavan5 to be revealed. Formation of amyloid plaques (APs) and neurofibrillary tangles (NFTs) are Farzana Rizwan5 two central hallmarks in the AD. APs are the dense composites of β-amyloid protein (Aβ) Shajan Koshy5 which accumulates around the nerve cells. Moreover, NFTs are the twisted fibers containing hyperphosphorylated tau proteins present in certain residues of Aβ that build up inside the Girish Prabhu5 brain cells. Certain factors contribute to the aetiogenesis of AD by regulating insulin signaling 1 Department of Molecular Medicine, pathway in the brain and accelerating the formation of neurotoxic Aβ and NFTs via various Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; mechanisms, including GSK3β, JNK, CamKII, CDK5, CK1, MARK4, PLK2, Syk, DYRK1A, 2Department of Pharmacology and PPP, and P70S6K. Progression to AD could be influenced by insulin signaling pathway that is Therapeutics, School of Medicine, affected due to T2DM. Interestingly, NFTs and APs lead to the impairment of several crucial Faculty of Health and Medical Sciences, Taylor’s University, Subang cascades, such as synaptogenesis, neurotrophy, and apoptosis, which are regulated by insulin, Jaya, Malaysia; 3Department of cholesterol, and glucose metabolism. The investigation of the molecular cascades through Pharmacology and Therapeutics, insulin functions in brain contributes to probe and perceive progressions of diabetes to AD. Faculty of Medicine, Dentistry and Health Sciences, The University This review elaborates the molecular insights that would help to further understand the potential of Melbourne, Parkville, VIC, mechanisms linking T2DM and AD. Australia; 4Malaysian Institute of Pharmaceuticals and Nutraceuticals Keywords: Alzheimer’s disease, type 2 diabetes mellitus, insulin deficiency, insulin signaling (IPharm), Bukit Gambir, Gelugor, Pulau pathway, cholesterol Pinang, Malaysia; 5School of Medicine, Faculty of Health and Medical Sciences, Taylor’s University, Subang Introduction Jaya, Malaysia Many reports suggest a strong pathophysiological links between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD). Prevalence of T2DM and its asso- ciated complications leads to AD that increases with time in the aging population, with profound oxidative stress (OS) potentially relating the molecular mechanisms involved in T2DM–AD linkage.1,2 Insulin action in the brain stimulates the modulation of numerous molecular cascades, such as cholesterol metabolism, energy expenditure, Correspondence: Aditya Arya glucose homeostasis, feeding behavior, synaptogenesis, neurotrophy, neurotransmitters, Department of Pharmacology and cognition, memory, inflammation, apoptosis, and reproduction.3 In addition, insulin Therapeutics, School of Medicine, Faculty regulates the metabolism of peripheral -amyloid peptide (A ) and hyperphosphory- of Health and Medical Sciences, Taylor’s β β University, Lakeside Campus, No.1, Jalan lated tau protein. In AD, the extracellular accumulation of Aβ plaques, intracellular Taylor’s, Subang Jaya, Malaysia aggregation of hyperphosphorylated tau protein in neurofibrillary tangles (NFTs), and Tel +60 3 5629 5653 Email [email protected] neuronal loss occur in the cortex and hippocampus.4,5 Hence, the disruption of insulin submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2018:12 3999–4021 3999 Dovepress © 2018 Rad et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/DDDT.S173970 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Rad et al Dovepress functions in diabetic conditions, like hyperinsulinemia and regeneration of axons, and neurite outgrowth in developing hyperglycemia, interrupts insulin signaling involved in the neurons projections as they grow (Figure 1).8,17,18 clearance of Aβ plaques and NFTs pathology. This leads to the accelerated formation of neurotoxic Aβ and NFTs Cholesterol metabolism via various mechanisms, including GSK3β, JNK, CamKII, Cholesterol which is metabolized in the brain plays a crucial CDK5, CK1, MARK4, PLK2, Syk, DYRK1A, PPP, and role in cell membrane, independent from peripheral tissues P70S6K contributing to the aetiogenesis of AD.1,2,6 In this featuring BBB, where it plays important membrane func- review, we discuss the roles of aberrant brain insulin sig- tion, acts as an antioxidant, and serves as the raw material naling in T2DM leading to AD and the mechanisms in the to produce steroidal progesterone which modulates neuroen- deposition of Aβ and NFTs and their therapeutic potential in docrine functions that alter physiology and behavior in the restoring the brain pathways that might contribute to T2DM CNS. Interestingly, in adipose tissue breakdown of fat is and AD treatment. inhibited by insulin which is responsible for the intracellular lipase inhibition that demands triglycerides to hydrolyze Insulin hormone linking type 2 diabetes and release fatty acids. Moreover, insulin stimulates entry and AD of glucose into adipocytes to synthesize glycerol within the The excessive insulin finds way into the brain and inter- cells, thereby enhancing the rate of glucose translocation rupts the biochemistry.7–9 One of the possible mechanisms across the cell membrane, muscles, and in adipose tissue. could be the modification of insulin signaling involved in Then, apolipoprotein E (ApoE)-cholesterol particle is pro- a variety of neuronal functions of brain, such as abnormal cessed to free the cholesterol in the lysosomes and is then protein O-GlcNAcylation, alteration of mitochondria, OS, transported to the membrane. ApoE isoform ε4 is the most glucose metabolism, and cholesterol, as well as amyloid common risk factor for AD that correlates with escalation of plaques (APs) formation, changed Aβ metabolism, and Aβ clearance and accumulation in the brain during AD.19–22 tau hyperphosphorylation protein deposition.1,8,10 Reduced Thus, insulin alteration in diabetes can interrupt brain choles- insulin plasma levels in T2DM can impair this signaling terol metabolism leading to metabolic dysfunction, thereby pathway forming two core neuropathological hallmarks causing neurological disorders (Figure 2).23 of AD, ie, NFTs and Aβ plaque, which leads to impaired memory and cognitive dysfunction.11,12 The progression of Glucose uptake diabetes to AD and their molecular cascades involved in the Uptake of glucose, the main fuel in body, varies among the function of insulin are discussed below (Table 1). tissues depending on the tissue metabolic needs and glucose availability. The glucose transporter (GLUT) protein iso- Insulin and brain forms are involved in facilitating the translocation of glucose Regulation of carbohydrate and fat metabolism is medi- in which the prominent isoforms are GLUT1-4. Glucose ated by insulin hormone via stimulating the absorption of uptake is stimulated by the movement of GLUT4 transporters glucose from the blood to fat tissue and skeletal muscles. from the intracellular membrane into the plasma membrane Disturbance in insulin in the periphery system may cause which demands GLUT4-containing vesicles to facilitate the diabetic mellitus (DM), but in the brain develop certain process.24 In the kidney, glucose uptake is accomplished by neurodegenerative states like mild cognitive impairment the secondary active transport mechanism through GLUT2 (MCI) and AD. However, brain itself can also synthesize transporter, linked to Na+/K+ pump reliant on the sodium some portion of insulin and crosses the blood–brain barrier gradient generated by NaKATPase. Malfunctioning of (BBB) through a saturable transporter within the central GLUT4 protein in the hippocampus affects the biochemical nervous system (CNS) that affects feeding and cognition reactions and cognitive flexibility offered by hippocampal through CNS mechanisms that are independent of glucose neurons, thus developing depression and lowering the cogni- utilization.3,8,13,14 Studies on the mechanisms of insulin pro- tive function which in turn increases the risk of Alzheimer duction and secretion in the CNS show similarities between development (Figure 3).25–27 beta cells and neurons, remarkably in the context of ATP-
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