European Neuropsychopharmacology (2014) 24, 1954–1960

www.elsevier.com/locate/euroneuro

Type 3 is sporadic Alzheimer's : Mini-review

Suzanne M. de la Monten

Departments of Medicine, Pathology, , 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 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 ; insulin responsiveness, glucose utilization, and energy metabolism, which lead to increased Alzheimer's; oxidative , inflammation, and worsening of . 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 , 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 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, 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 , impairments in home- with the initial stages of cognitive dysfunction (Hoyer, ostasis, and increased . 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 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 ; 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- needed for cholinergic function, further compromis- siveness to insulin/IGF stimulation (Rivera et al., 2005; ing neuronal plasticity, , and (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 (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, and plasticity (de la cascades (de la Monte et al., 2009a; de la Monte and Monte et al., 2009a; de la Monte and Wands, 2005). Wands, 2005). Correspondingly, experimental depletion or 1956 S.M. de la Monte suppression of brain insulin receptor expression and func- functions and plasticity, and perturbation of signaling path- tion causes cognitive impairment and molecular and bio- ways for energy metabolism, homeostasis, and cell survival. chemical abnormalities seen in AD (de la Monte et al., 2011; Grunblatt et al., 2007; Hoyer et al., 2000; Labak et al., 2010; Lester-Coll et al., 2006). 5. Impaired insulin/IGF signaling and tau pathology in AD 4. Role of insulin/IGF resistance in brain metabolic dysfunction and oxidative stress in Neurofibrillary tangles and dystrophic neurites are the main AD neuronal cytoskeletal lesions that correlate with severity of dementia in AD (Duyckaerts et al., 2009; Takashima, 2009). Mechanistically, the microtubule-associated protein, tau, Insulin and IGF signaling regulate glucose utilization, meta- gets hyper-phosphorylated due to inappropriate activation bolism, and ATP synthesis needed for both homeostasis and of proline-directed kinases such as GSK-3β. Consequently, dynamic modulation of cellular functions (de la Monte and tau misfolds and self-aggregates into insoluble fibrillar Wands, 2005; Frolich et al., 1998). Consequently, brain structures (paired helical filaments and straight filaments) insulin/IGF resistance and deficiency are accompanied by that form neurofibrillary tangles, dystrophic neurites, and impairments in glucose utilization and disruption of energy neuropil threads (Iqbal et al., 2009). Intra-neuronal accu- metabolism, with attendant increases in oxidative stress, mulations of fibrillar tau disrupt neuronal cytoskeletal net- ROS production, DNA damage, and mitochondrial dysfunc- works and axonal transport, leading to synaptic tion, all of which drive pro-apoptosis, pro-inflammatory, and disconnection and progressive neurodegeneration (Iqbal pro-AβPP-Aβ cascades (de la Monte and Wands, 2006; Frolich et al., 2009). Besides fibrillar tau, pre-fibrillar tau can et al., 1998; Hoyer, 2002, 2004b; Rivera et al., 2005; Steen aggregate, forming soluble tau oligomers or insoluble gran- et al., 2005). Moreover, as AD progresses, cerebral glucose ular tau, which also contribute to neurodegeneration by utilization, responses to insulin signaling, and expression of causing synaptic disconnection and neuronal death insulin-responsive genes decline (Rivera et al., 2005; Talbot (Takashima, 2010). The eventual ubiquitination of hyper- et al., 2012). Correspondingly, experimental depletion or phosphorylated tau (Arnaud et al., 2006), combined with suppression of brain insulin receptor expression and func- dysfunction of the ubiquitin–proteasome system (Oddo, tion causes cognitive impairment and AD-type neurodegen- 2008), causes further accumulations of insoluble fibrillar eration (de la Monte et al., 2011; Grunblatt et al., 2007; tau, oxidative stress, and ROS generation, leading to Hoyer et al., 2000; Labak et al., 2010; Lannert and Hoyer, increased neuronal apoptosis, mitochondrial dysfunction, 1998; Lester-Coll et al., 2006). and necrosis in AD (Mandelkow et al., 2003). Brain glucose uptake and utilization are mediated by Growing evidence suggests that many of the aforemen- glucose transporter (GLUT) proteins, whose expression and tioned cellular aspects of AD neurodegeneration can be function are regulated by insulin. GLUT4 is abundantly mediated by brain insulin/IGF resistance (de la Monte et al., expressed along with insulin receptors, in medial temporal 2000, 2001; de la Monte and Wands, 2002; Rivera et al., structures, which are notable targets of AD. Insulin stimu- 2005; Steen et al., 2005; Xu et al., 2003). Tau expression lates GLUT4 expression and protein trafficking from the and phosphorylation are regulated by insulin and IGF cytosol to the plasma membrane to modulate glucose (Schubert et al., 2003, 2004). In AD, brain insulin and IGF uptake and utilization (Gonzalez-Sanchez and Serrano-Rios, resistance reduce signaling through phosphoinositol-3- 2007). Therefore, insulin stimulation of GLUT4 is critical for kinase (PI3K), Akt (Schubert et al., 2003, 2004), and Wnt/ regulating neuronal metabolism and energy production β-catenin (Doble and Woodgett, 2003), and increases acti- which are needed for memory and cognition. Despite vation of GSK-3β (De Ferrari and Inestrosa, 2000; Fraser evidence for brain insulin resistance and deficiency in AD, et al., 2001; Grilli et al., 2003; Mudher et al., 2001; postmortem brain studies have not detected reduced levels Nishimura et al., 1999). GSK-3β over-activation is partly of GLUT4 expression (Steen et al., 2005). Instead, the well- responsible for the hyper-phosphorylation of tau, which documented deficits in brain glucose utilization and promotes tau misfolding and fibril aggregation (Bhat energy metabolism vis-a-vis brain insulin/IGF resistance et al., 2003). In addition, AD tau pathology is mediated by could be mediated by impairments in GLUT4 trafficking impaired tau gene expression due to reduced insulin and IGF between the cytosol and plasma membrane (Winocur et al., signaling (de la Monte et al., 2003). Consequences include 2005). failure to generate sufficient quantities of normal soluble Deficiencies in energy metabolism caused by inhibition of tau vis-a-vis accumulation of hyper-phosphorylated insolu- insulin/IGF signaling promote oxidative stress, mitochon- ble fibillar tau, and attendant exacerbation of cytoskeletal drial dysfunction, and pro-inflammatory cytokine activation collapse, neurite retraction, and synaptic disconnection. (de la Monte and Wands, 2002; Hoyer and Lannert, 1999; Hoyer et al., 2000). Oxidative stress leads to the generation and accumulation of ROS and reactive nitrogen species, which attack subcellular organelles and cause chemical 6. Insulin/IGF resistance and amyloid-beta modifications of DNA, RNA, lipids, and proteins. For exam- (AβPP-Aβ) neurotoxicity ple, adducts formed with macromolecules can compromise the structural and functional integrity of neurons due to loss AD is associated with dysregulated expression and proces- of membrane functions, disruption of the cytoskeleton, sing of amyloid precursor protein (AβPP), resulting in the dystrophy of synaptic terminals, deficits in neurotransmitter accumulation of neurotoxic AβPP-Aβ oligomeric fibrils or Type 3 diabetes is sporadic Alzheimer's disease: Mini-review 1957 insoluble larger aggregated fibrils (plaques). Increased AβPP rats were administered intracerebroventricular injections of gene expression, together with altered proteolysis, leads to streptozotocin, a pro-diabetes drug. Streptozotocin treated accumulations of 40 or 42 amino acid length AβPP-Aβ rats develop cognitive impairment with deficits in spatial peptides that can aggregate. In familial AD, mutations in learning and memory, brain insulin resistance and insulin the AβPP, presenilin 1 (PS1), or PS2 genes, and inheritance deficiency, and AD-type neurodegeneration (Hoyer et al., of the Apoliprotein E ε4 (ApoE- ε4) allele promote AβPP-Aβ 1999; Lester-Coll et al., 2006; Weinstock and Shoham, accumulation in the brain. In sporadic AD, which accounts 2004). Therefore, targeted exposure to a pro-diabetes drug for 90% or more of the cases, the causes of AβPP-Aβ can cause neurodegeneration with structural, molecular, accumulation are not well understood. However, recent biochemical and functional abnormalities that closely mimic evidence points to brain insulin/IGF resistance as both the pathology of AD in humans. causal and consequential factors. This line of research was extended based upon the facts Studies have shown that insulin stimulation promotes that streptozotocin is a nitrosamine-related compound, and trafficking of AβPP-Aβ from the trans-Golgi network where over the past several decades, Western societies have been it originates, to the plasma membrane for extracellular assaulted by continuous and escalated contacts with envir- secretion (Watson et al., 2003). In addition, insulin inhibits onmental, agricultural, and food source nitrates and nitrites AβPP-Aβ's intracellular accumulation and degradation by that result in increased nitrosamine exposures (de la Monte insulin-degrading enzyme (Gasparini et al., 2001, 2002). et al., 2009b). We found that experimental exposures Impairments in insulin signaling disrupt AβPP processing and to low, sub-mutagenic doses of the nitrosamines that AβPP-Aβ clearance in the brain (Messier and Teutenberg, can be found in processed and preserved foods, e.g. 2005). Accumulation of AβPP-Aβ further compromises insulin N-nitrosodiethylamine (NDEA), cause cognitive impairment, signaling by decreasing insulin's binding affinity to its own AD-type neurodegeneration, and brain insulin resistance (de receptor, worsening effects of insulin resistance (Ling et al., la Monte et al., 2009c; Tong et al., 2009, 2010), similar to 2002; Xie et al., 2002). Furthermore, AβPP-Aβ oligomers the effects of streptozotocin. Therefore, nitrosamine- inhibit neuronal transmission of insulin-stimulated signals by related chemicals can cause Type 3 diabetes, mimicking desensitizing and reducing the surface expression of insulin the abnormalities seen in sporadic AD. We postulate that receptors. Finally, intracellular AβPP-Aβ directly interferes the rapid increases in prevalence rates of sporadic AD (Type with PI3 kinase activation of Akt, impairing neuronal survival 3 diabetes) are due to environmental exposures such as and increasing GSK-3β activation and hyper-phosphorylation nitrosamines that contaminate highly processed and pre- of tau. As discussed, hyper-phosphorylated tau is prone served foods and have become staples in our diets over the to misfold, aggregate, and become ubiquitinated, prompting past 50 years (de la Monte and Tong, 2009). Further research the formation of dementia-associated paired-helical is needed to better assess the impact of such exogenous filament-containing neuronal cytoskeletal lesions. mediators of neurodegeneration, and the spectrum of agents that can produce similar abnormalities leading to AD-type neurodegeneration. 7. Potential mechanisms of brain insulin/IGF resistance in neurodegeneration Conflict of interest

Although aging is clearly the dominant for AD, No conflict of interest to declare. growing evidence suggests that brain insulin/IGF resistance is a major factor contributing to mild cognitive impairment, Contributions dementia, and AD (Craft, 2005b, 2006; de la Monte et al., 2009a; Hoyer et al., 1991; Rivera et al., 2005). Over the past several years, this field of research has greatly Suzanne M. de la Monte. expanded due to growing information about the causes and consequences of brain insulin resistance and deficiency Role of funding in relation to cognitive impairment (Craft, 2005a, 2006, 2007; de la Monte et al., 2006; Lester-Coll et al., 2006; Supported by AA11431 and AA12908 from the National Rivera et al., 2005; Steen et al., 2005). A convincing Institutes of Health. argument could be made that AD, in its pure form, represents a brain form of diabetes mellitus (Craft, 2007; Acknowledgment Hoyer, 2002; Hoyer et al., 1991; Rivera et al., 2005; Steen et al., 2005) since AD is often associated with progressive Supported by AA11431 and AA12908 from the National Institutes of brain insulin resistance in the absence of Type 2 diabetes, Health. , or peripheral insulin resistance (de la Monte, 2011; de la Monte et al., 2009a; Rivera et al., 2005; Steen et al., References 2005). Moreover, postmortem studies demonstrated that the molecular, biochemical, and signal transduction abnormal- Arnaud, L., Robakis, N.K., Figueiredo-Pereira, M.E., 2006. It may ities in AD are virtually identical to those in Type 1 and Type take inflammation, phosphorylation and ubiquitination to ‘tan- 2 diabetes mellitus (Rivera et al., 2005; Steen et al., 2005; gle’ in Alzheimer's disease. Neurodegener. Dis. 3, 313–319. Talbot et al., 2012). Baker, L.D., Cross, D.J., Minoshima, S., Belongia, D., Watson, G.S., The strongest evidence favoring the concept that AD is Craft, S., 2011. Insulin resistance and Alzheimer-like reductions Type 3 diabetes comes from experimental studies in which in regional cerebral glucose metabolism for cognitively normal 1958 S.M. de la Monte

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