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Type 3 Diabetes Is Sporadic Alzheimer׳S Disease Mini-Review

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Type 3 Diabetes Is Sporadic Alzheimer׳S Disease Mini-Review European Neuropsychopharmacology (2014) 24, 1954–1960 www.elsevier.com/locate/euroneuro Type 3 diabetes is sporadic Alzheimer's disease: Mini-review Suzanne M. de la Monten Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, 55 Claverick Street, Room 419, Providence, RI 02903, USA Received 12 June 2014; accepted 20 June 2014 KEYWORDS Abstract Insulin resistance; Alzheimer's disease (AD) is the most common cause of dementia in North America. Growing Diabetes; evidence supports the concept that AD is a metabolic disease mediated by impairments in brain Glucose Metabolism; insulin responsiveness, glucose utilization, and energy metabolism, which lead to increased Alzheimer's; oxidative stress, inflammation, and worsening of insulin resistance. In addition, metabolic Nitrosamines derangements directly contribute to the structural, functional, molecular, and biochemical abnormalities that characterize AD, including neuronal loss, synaptic disconnection, tau hyperphosphorylation, and amyloid-beta accumulation. Because the fundamental abnormalities in AD represent effects of brain insulin resistance and deficiency, and the molecular and biochemical consequences overlap with Type 1 and Type 2 diabetes, we suggest the term “Type 3 diabetes” to account for the underlying abnormalities associated with AD-type neurodegen- eration. In light of the rapid increases in sporadic AD prevalence rates and vastly expanded use of nitrites and nitrates in foods and agricultural products over the past 30–40 years, the potential role of nitrosamine exposures as mediators of Type 3 diabetes is discussed. & 2014 Elsevier B.V. and ECNP. All rights reserved. 1. Alzheimer's disease and brain glucose Disorders and Stroke and the Alzheimer's Disease and starvation Related Disorders Association (NINCDS/ADRDA) and DSM-IV criteria (Cummings, 2007). Although neuroimaging and biomarker panels begin to facilitate its detection and Sporadic Alzheimer's disease (AD) is the most common cause severity (Gustaw-Rothenberg et al., 2010), a definitive of dementia in North America and its high incidence and diagnosis can only be rendered by postmortem examination prevalence rates now constitute an epidemic (de la Monte of the brain. AD presence and severity are gauged by the et al., 2009b). AD diagnosis is based on criteria set by distribution and abundance of related and characteristic the National Institute of Neurological and Communicative lesions, including neuronal loss, gliosis, insoluble aggregates of abnormally phosphorylated and ubiquitinated tau in the nTel.: +1 401 444 7364; fax: +1 401 444 2939. forms of neurofibrillary tangles, dystrophic neurites and E-mail address: [email protected] neuropil threads, and neurotoxic amyloid-beta precursor http://dx.doi.org/10.1016/j.euroneuro.2014.06.008 0924-977X/& 2014 Elsevier B.V. and ECNP. All rights reserved. Type 3 diabetes is sporadic Alzheimer's disease: Mini-review 1955 protein peptides (AβPP-Aβ) as oligomers, fibrillar aggre- The anti-apoptosis mechanisms that insulin/IGF-1 inhibit gates, or extracellular plaques. Secreted AβPP-Aβ oligomers include BAD (inhibitor of Bcl-2), Forkhead Box O (FoxO), are neurotoxic and inhibit synaptic plasticity (Walsh et al., glycogen synthase kinase 3β (GSK-3β), and nuclear factor 2002). Beyond these effects, AD is associated with degen- kappa B (NF-κB) (de la Monte et al., 2009a). GSK-3β regulates eration and disconnection of synaptic terminals, disruption Wnt signaling by phosphorylating β-catenin, leading to its of the cortical laminar architecture, neuro-inflammation, degradation via the ubiquitin–proteasome pathway (Cadigan and white matter fiber loss. and Liu, 2006; Foltz et al., 2002). Since Wnt mediates Over decades, the dominant hypothesis was that neuro- synaptic plasticity (Contestabile et al., 2013; Tabatadze degeneration is caused by one or two of the specific lesions et al., 2012; Varela-Nallar and Inestrosa, 2013), impairments that characterize AD, e.g. AβPP-Aβ accumulation, pTau in insulin/IGF signaling compromise cross-talk with various aggregation, or neuro-inflammation. However, a stream of Wnt functions in the brain. In essence, insulin/IGF pathways human and experimental studies has provided convincing support neuronal growth, survival, differentiation, migra- evidence that AD is a metabolic disease whereby the brain tion, energy metabolism, gene expression, protein synthesis, loses its capacity to efficiently utilize glucose for energy cytoskeletal assembly, synapse formation, neurotransmitter production and respond to critical trophic factor signals due function, and plasticity (Chesik et al., 2008; de la Monte and to insulin as well as insulin-like growth factor (IGF) resis- Wands, 2005; Gong et al., 2008; Liang et al., 2007). tance (Baker et al., 2011; Craft, 2007; Hoyer, 2002, 2004b; Correspondingly, impaired insulin/IGF signaling has dire Krikorian et al., 2010; Luchsinger, 2010; Neumann et al., effects on the CNS's structural and functional integrity. 2008; Rivera et al., 2005; Schubert et al., 2004; Steen et al., 2005; Talbot et al., 2012; Watson and Craft, 2006). The molecular and biochemical consequences of insulin and 3. Evidence of type 3 diabetes (brain insulin IGF resistance in the brain are similar to those in other and IGF resistance and deficiency) in AD organs and tissues; however, in brain, insulin signaling impairments compromise neuronal survival, energy produc- The concept that AD represents a metabolic disease tion, gene expression, plasticity and white matter integrity stemmed from studies showing that deficits in cerebral (de la Monte, 2011; de la Monte et al., 2009a). Since glucose glucose utilization were present very early in the course is the primary fuel for the brain, deficits in glucose uptake of disease (Caselli et al., 2008; Langbaum et al., 2010; and utilization cause the brain to “starve”. With the Mosconi et al., 2008, 2009), either prior to, or coincident starvation comes oxidative stress, impairments in home- with the initial stages of cognitive dysfunction (Hoyer, ostasis, and increased cell death. Inhibition of insulin/IGF 2004a; Iwangoff et al., 1980). Deficits in cerebral glucose signaling mediates AD neurodegeneration due to increased: utilization and energy metabolism worsen with progression 1) activity of kinases that aberrantly phosphorylate tau; 2) of cognitive impairment (Hoyer et al., 1991). Furthermore, accumulation of AβPP-Aβ; 3) oxidative and endoplasmic human postmortem studies revealed that brains from clini- reticulum (ER) stress; 4) generation of reactive oxygen cally well-characterized patients with pathologically proven and reactive nitrogen species that damage proteins, RNA, AD have molecular and biochemical evidence of insulin and DNA, and lipids; 5) mitochondrial dysfunction; and 6) IGF resistance and deficiencies, as well as impairments in signaling through pro-inflammatory and pro-apoptosis cas- signal transduction (Rivera et al., 2005; Steen et al., 2005). cades (de la Monte, 2011, 2012; de la Monte et al., 2009a, Brain insulin/IGF resistance is manifested by reduced 2012). In addition, insulin resistance down-regulates target levels of insulin/IGF receptor binding and decreased respon- genes needed for cholinergic function, further compromis- siveness to insulin/IGF stimulation (Rivera et al., 2005; ing neuronal plasticity, memory, and cognition (de la Monte, Steen et al., 2005; Talbot et al., 2012), while insulin/IGF 2011; de la Monte et al., 2009a). deficiencies are associated with altered expression of insulin and IGF polypeptides in brain and cerebrospinal fluid (Hoyer, 2004a,b; Rivera et al., 2005; Steen et al., 2005). 2. Insulin and IGF actions in the brain These findings support the concept that chronic deficits in insulin signaling mediate the pathogenesis of AD (Steen In the central nervous system (CNS), insulin and IGF signal- et al., 2005). Moreover, AD could be regarded as a brain ing pathways play critical roles in cognitive function. disorder that has composite features of Type 1 (insulin Insulin, IGF-1 and IGF-2 polypeptide and receptor genes deficiency) and Type 2 (insulin resistance) diabetes. To are expressed in neurons (de la Monte and Wands, 2005) and consolidate this concept, we proposed that AD be referred glial cells (Broughton et al., 2007; Freude et al., 2009; to as, “Type 3 diabetes” (Rivera et al., 2005; Steen et al., Zeger et al., 2007) throughout the brain; their highest levels 2005). As insulin stimulates brain glucose uptake and are in structures that are heavily targeted by neurodegen- utilization (de la Monte and Wands, 2005), metabolism, eration, particularly AD (de la Monte et al., 2009a; de la memory, and cognition (Benedict et al., 2004; Craft et al., Monte and Wands, 2005). Insulin and IGFs regulate a wide 2003; Krikorian et al., 2010; Reger et al., 2006, 2008), range of neuronal functions through ligand–receptor binding insulin resistance/deficiency associated impairments in glu- and activation of intrinsic receptor tyrosine kinases. Sub- cose metabolism disrupt brain energy balance, increasing sequent interactions between phosphorylated receptors and oxidative stress, reactive oxygen species (ROS) production, insulin receptor substrate molecules mediate transmission DNA damage, and mitochondrial dysfunction, all of which of signals downstream, and thereby inhibit apoptosis, and drive pro-apoptosis, pro-inflammatory, and pro-AβPP-Aβ stimulate growth, survival, metabolism,
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