J Neural Transm DOI 10.1007/s00702-015-1377-5

NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE

The metabolism hypothesis of Alzheimer’s disease: from the concept of central insulin resistance and associated consequences to insulin therapy Katrin Morgen • Lutz Fro¨lich

Received: 30 October 2014 / Accepted: 4 February 2015 Ó Springer-Verlag Wien 2015

Abstract The concept of central insulin resistance and dysfunctional insulin signaling in Alzheimer’s disease (AD) has been developed by Siegfried Hoyer in 1985–2000. It is widely recognized that a cerebrometabolic deficiency is one of the most relevant proximate characteristics of sporadic AD, including functional deficits in oxidative glucose breakdown, oxidative stress and amplifying the action of glucocorticoids in the brain. Insulin and insulin receptors are widely distributed in the brain and are impaired in the post-mortem Alzheimer brain. Functionally, altered insulin signaling may promote synaptic dysfunction and impaired connectivity, especially in highly connected and metabolically active regions of the brain, which in turn predisposes towards AD pathology. Thus, the hypothesis has been proposed that defects in the brain insulin signal transduction system and associated consequences, e.g., oxidative stress, are centrally involved in the etiopathogenesis of sporadic AD. Most importantly, in a research field still awaiting substantial progress in therapeutic options, the idea of AD as a brain type of diabetes mellitus is now being translated into clinical trials with promising early results. Keywords Alzheimer’s disease
Insulin
Insulin receptors
Glucose metabolism
Synaptic dysfunction
Connectivity

K. Morgen
L. Fro¨lich (&) Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159 Mannheim, Germany e-mail: [email protected] K. Morgen e-mail: [email protected]

Introduction When Siegfried Hoyer postulated that dysfunctional insulin signaling restricted to the brain caused Alzheimer’s disease (AD), he challenged established notions of amyloid/tau-based pathology as the primary cause of Alzheimer pathology. The recognition that AD is a heterogeneous disorder that results from incremental pathological changes in dynamic organismic systems is increasingly recognized as an integrating concept for this highly prevalent neurodegenerative disease. Furthermore, it may have important therapeutic implications to extend the unidimensional approaches to prevention and therapy. His primary assumption was that excess formation of bA4 has not been proven to be necessary for generation and the development of sporadic AD (Joseph et al. 2001). Instead, there is increasing evidence that a cerebrometabolic deficiency is the most relevant proximate cause of sporadic AD (Blass et al. 2002). In this context, several susceptibility genes may contribute to the pathogenesis, e.g., the apolipoprotein E (APOE) polymorphism on chromosome 19. Also, in sporadic AD, single nucleotide polymorphism has been found in the gene coding for 11b-hydroxysteroid dehydrogenase I which is associated with a sixfold increased risk for sporadic AD (de Quervain et al. 2004). This enzyme acts as a dehydrogenase/reductase, catalyzing the interconversion of active glucocorticoids and inert 11-keto forms (dehydrogenase), and regenerating active glucocorticoids from inert 11-keto forms (reductase) (Duax et al. 1996; Jellinck et al. 1999). In the brain, 11b-hydroxysteroid dehydrogenase I acts predominantly as a reductase thus amplifying the glucocorticoid action (Seckl and Walker 2001). Several other potential candidate susceptibility genes whose contributory

123

K. Morgen, L. Fro¨lich

significance is speculative as yet, contribute to etiopathogenesis of sporadic AD (Lambert et al. 2013).

Impaired cerebral glucose metabolism in sporadic AD Starting from findings of impaired cerebral glucose metabolism in sporadic AD (Hoyer et al. 1988, 1991), it could be shown that this functional disturbance is accompanied by impaired enzyme activities of the key regulatory enzymes of cerebral glucose breakdown (Blass et al. 2002; Fro¨lich et al. 2004). In recent years, it has become increasingly clear that Hoyer’s findings on the significance of an impaired cerebral glucose metabolism in the development of AD, in fact, complement other known AD mechanisms, e.g., oxidative stress and glucocorticoid-related neurodegeneration. Based on several experimental and post-mortem brain studies (for review see Hoyer and Fro¨lich 2007), the hypothesis has been proposed that the brain insulin signal transduction system is centrally involved in the etiopathogenesis of sporadic AD (Hoyer 2002). Most importantly, in a research field still awaiting substantial progress in therapeutic options, the idea of AD as a brain type of diabetes mellitus (Lee et al. 2013) is now being translated into clinical trials with promising early results.

Insulin signaling and functional effects on brain glucose and energy metabolism in experimental models Acute stimulation of the cerebral insulin receptor may be achieved through a single intracerebroventricular injection of insulin in rat models. This procedure led to a dosedependent stimulation of the glycolytic key enzymes hexokinase and phosphofructokinase in the cerebral cortex (Hoyer et al. 1993). Also, acute stimulatory effects of the hormone in the brain have been demonstrated for pyruvate dehydrogenase (Rinaudo et al. 1987) and choline acetyltransferase (Kyriakis et al. 1987). These data may indicate that both glycolytic flux and pyruvate oxidation in the brain are stimulated by insulin paralleling the hormone’s effect in non-nervous tissue. Short-term (1 day) or longterm (7 and 21 days) intracerebroventricular infusion of insulin have been found to exhibit a discrete anabolic effect on energy metabolism in the hippocampus (Henneberg and Hoyer 1994). Of great functional importance and closely related to energy metabolism is the regulation of the Na?/K?-ATP-ase by insulin, since the Na?,K?pump modulates membrane potential in all mammalian cells, which in turn drives ion-coupled transport processes and maintains cell volume and osmotic balance (Sweeney and Klip 1998).

123

Insulin signaling interacts with cellular messenger systems involved in AD The insulin/insulin receptor-mediated signal transduction controls the activity of several enzymes in a cascade-like manner (Avruch 1998). Phosphatidylinositol 3-kinase is insulin-regulated and activated by protein kinase B (Alessi and Cohen 1998; Vanhaesebroeck and Alessi 2000). This latter enzyme regulates the activity of the glycogen synthase kinases (GSK) 3a and 3b (Cross et al. 1995, 1997). The insulin-stimulated signal decreased the activity of GSK-3a by about 50 % (Ramakrishna and Benjamin 1998), and GSK-3ß by about 70 %, obviously by phosphorylation of the serine-9 residue through the S6 kinase. The inhibition of both enzymes was reversed by protein phosphatase 2A dephosphorylating the GSKs at serine-9 (Welsh and Proud 1993; Sutherland and Cohen 1994). GSK-3a is inhibited by phosphorylation at serine21, GSK3ß by phosphorylation at serine-9 (for review see Cohen and Frame 2001). GSK-3 is constitutively phosphorylated at tyrosine279 (GSK-3a) and at tyrosine216 (GSK-3ß) which is associated with an activation. Dephosphorylation of these tyrosine residues induces the inactivation of this enzyme (Hughes et al. 1993; Bhat et al. 2000). Interestingly, the inhibition of protein phosphatase-1 being involved to a lesser extent in the regulation of tau-protein phosphorylation inhibited up to about 80 % of GSK-3 activity (Bennecib et al. 2000). Independently from insulin, cAMP-dependent protein kinase A exerts the same effect on both GSK-3a and-3ß, as does the insulin-stimulated protein kinase B (Fang et al. 2000; Li et al. 2000). GSK-3 has turned out to play a key role in numerous cell functions including the metabolism of the amyloid precursor protein (APP) and the regulation of tau-protein phosphorylation. Furthermore, much more widespread effects on vascular function, lipid metabolism, and inflammation/oxidative stress may all be related to changes of cellular messenger systems controlled by insulin (for review see Craft et al. 2013).

Insulin signaling and amyloid pathology interact in conferring risk of AD Insulin receptor signaling in the central nervous system (CNS) has been found to be essential for the maintenance of excitatory synaptic transmission and for experiencedriven structural plasticity (Chiu et al. 2008). While insulin receptors are ubiquitous in the CNS, their density has been found to be especially high in the olfactory bulb, entorhinal cortex, piriform cortex, hippocampus, amygdala, arcuate nucleus of the hypothalamus, cerebellum, choroid plexus and frontal cortex (Havrankova et al. 1978; Marks et al.

The metabolism hypothesis of AD

1990; Schechter et al. 1992, 1996). The distribution of insulin receptors in the brain is consistent with a prominent impact of insulin on cognition, specifically with predominant effects on memory, executive function and mood (Baskin et al. 1987; Benedict et al. 2004). In patients with AD, there is evidence for reduced levels of CNS insulin and impaired CNS insulin receptor function (Fro¨lich et al. 1998, 1999). A close link between this central insulin resistance and amyloid pathology has become increasingly apparent. Amyloid beta oligomers have been shown to bind to insulin receptors and cause them to shift from the surface to the center of the cell, thereby impeding glutamatergic neurotransmission (Schubert et al. 2004; Plum et al. 2005). More recently, amyloid beta oligomers were found to inactivate insulin receptors via c-Jun N-terminal kinase (Ma et al. 2009; Freiherr et al. 2013), comparable to an established peripheral effect of c-Jun N-terminal kinase on insulin receptors in diabetes mellitus (Manolopoulos et al. 2010). Conversely, insulin signaling protects synapses against amyloid beta effects by reducing the number of binding sites (De Felice et al. 2009; Freiherr et al. 2013).

Altered brain insulin signaling and the phenomenon of brain network dysfunction in AD Because of its excitatory effect on synaptic transmission, insulin is essential for brain network function. Altered insulin signaling may promote synaptic dysfunction and impaired connectivity, early features of AD (e.g., Scheff et al. 2006; Marcello et al. 2012), before neuronal loss occurs. While hippocampal disconnection has been established as a neural substrate of memory impairment even early on in the disease (Scheff et al. 2006), functional imaging techniques, such as fMRI-based small worldness analyses (Supekar et al. 2008), have confirmed global changes in brain organization in AD. Functionally, AD is associated with synaptic failure, which is regarded the major proximal cause for the typical loss of declarative and non-declarative memory and leading to brain atrophy over an extended period of time (Selkoe 2002). Long-term potentiation (LTP) and long-term depression (LTD) are considered the major cellular mechanism involved in synaptic plasticity and learning and memory (Malenka 1994). In AD, LTP is inhibited and long-term depression (LTD) is enhanced by b-amyloid oligomers, the major toxic species of amyloid peptides (Shankar et al. 2008). Of note, highly connected regions in the brain tend to exhibit increased metabolism and activity, which in turn appears to predispose towards AD pathology. Even in subjects with mild cognitive impairment, cortical hubs including hippocampus, precuneus/posterior cingulate

cortex, lateral temporal and parietal and prefrontal cortex show an increased susceptibility to amyloid deposition, which has been linked to their high metabolism and neural activity (Buckner et al. 2009; de Haan et al. 2012). Both factors, the susceptibility of highly connected and active regions to amyloid pathology and the ubiquitous impairment of CNS insulin signaling presumably contribute to the global disruption of network function in AD. Considering that pronounced changes in brain connectivity are detectible even in prodromal AD and precede widespread neuronal loss (Supekar et al. 2008), the substitution of CNS insulin as a neuroprotective agent that promotes synaptic integrity and function is an appealing concept.

Dysfunctional insulin signaling in AD as avenue for treatment Recent studies have indicated that intranasally applied insulin modulates insulin receptor signaling without the risk of hypoglycemia or insulin resistance (Stockhorst et al. 2004, 2011; Reger et al. 2008). In healthy subjects, the intranasal (IN) administration of insulin has been shown to reduce caloric intake, enhance memory function and mood acutely, i.e., after a single administration, as well as after prolonged daily treatment (Benedict et al. 2004, 2008). Of note, these effects may be gender-dependent; thus a reduction in caloric intake after a single application of IN insulin was only observed in men in a study by Benedict et al. (2008), whereas an improvement in declarative memory function occurred only in the female subgroup. In another study involving an 8-week daily treatment with IN insulin, both genders exhibited enhanced declarative memory at a high daily dose of 4 9 40 IU (Benedict et al. 2004). AD patients also show a beneficial effect on memory function from the acute as well as longer-term daily administration of IN insulin. In a pilot clinical trial, patients with AD benefited significantly from the daily intranasal administration of insulin compared to a placebo-group regarding verbal memory after 4 months of daily treatment (Craft et al. 2012). An immediate improvement in delayed recall has been observed specifically in APOE-negative AD patients, though genotype effects need to be confirmed in larger studies (Reger and Craft 2006). While healthy subjects and AD patients both exhibit cognitive effects from IN insulin, the optimal dose may depend on disease status. Thus, AD patients showed improved delayed verbal recall immediately after a single treatment with 20 IU of IN insulin, but not after the administration of 60 IU In fact, 60 IU of insulin reduced performance in APOE-E4 carriers with AD. In contrast, healthy controls have shown

123

K. Morgen, L. Fro¨lich

beneficial working memory effects most consistently with high daily doses of 160 IU of IN insulin (Benedict et al. 2004; Shemesh et al. 2012). Because of the encouraging results of the 4-month pilot trial on the effects of intranasally applied insulin (Craft et al. 2012), a larger multi-center trial including 240 subjects with mild cognitive impairment or AD is now one of two AD trials receiving large-scale government funding based on the US National Alzheimer’s Plan (ClinicalTrials.gov Identifier: NCT01767909; Wadman 2012). In this double-blind and placebo-controlled phase II/III trial, subjects will be treated with intranasal insulin or placebo for one year; subsequently all subjects will receive the active drug for 6 months. Primary outcome measures include effects on cognitive status, brain structure on MRI, changes in cerebrospinal fluid (CSF) AD markers and significance of gender and APOE E4 status for insulin response.

Alpha-lipoic acid, a therapeutic target downstream of insulin signal transduction Pyruvate dehydrogenase complex (PDHc) and ketoglutarate dehydrogenase complex (KGDHc) in brain tissue are key mitochondrial energy-related enzyme complexes regulated by insulin (Rinaudo et al. 1987). They are of particular interest in AD because their activity is reduced in post-mortem AD brain (Blass et al. 2002), a defect of functional importance (Ko et al. 2001). These and further data are consistent with a two-hit hypothesis of AD: oxidative stress due to impaired insulin signal transduction leads to lipid peroxidation that, in turn, causes oxidative dysfunction of key energy-related enzyme complexes in mitochondria, thus triggering neurodegeneration (Hardas et al. 2013). Thus, the development of AD pathology may not be solely due to disturbances in the insulin-IR-cascade and imbalance of the oxygen-glucose utilization, but as a consequence of such biochemical alterations oxidative stress (OS)-related mechanisms, may be initiated (Pratico` 2008; Chang et al. 2014). In particular, mitochondrial dysfunction, elevated iron concentration, reactive oxygen species (ROS), and stress-related enzymes or proteins (e.g., heme oxygenase-1, transferrin, etc.), are found in AD and can be linked to insulin deficient states (Gru¨nblatt et al. 2011). (r)-Alpha-lipoic acid is the most important co-factor for both enzymes and stimulates their activities in AD brain (Fro¨lich et al. 2004). In a randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha-lipoic acid (LA) in Alzheimer’s disease, the combination of x-3 ? LA slowed cognitive and functional decline in AD over 12 months (Shinto et al. 2014). There are two earlier

123

clinical trials, in which LA was given daily to 43 patients with AD (receiving standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of up to 48 months. There were some indications of a slowing of disease progression in patients with mild dementia (ADAScog \15) (Hager et al. 2001; Maczurek et al. 2008). Because LA has been shown to have a variety of properties which can interfere with pathogenic principles of AD (Holmquist et al. 2007), it remains another therapeutic target downstream of insulin signal transduction warranting further clinical testing.

Conclusion In conclusion, Hoyer’s innovative concept of AD as a brain type of CNS insulin resistance associated with a specific defect of the brain oxygen-glucose utilization and the detoxification systems for oxidative stress has resulted in several elegant therapeutic and perhaps preventive strategies in AD. Hopefully, the current, yet limited evidence in favor of intranasally applied insulin and/or moieties with antioxidative potential derived from LA may finally be translated into an effective treatment for the benefit of AD patients.

References Alessi DR, Cohen P (1998) Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev 8:55–62 Avruch J (1998) Insulin signal transduction through protein kinase cascades. Mol Cell Biochem 182:31–48 Baskin DG, Figlewicz DP, Woods SC, Porte D Jr, Dorsa DM (1987) Insulin in the brain. Annu Rev Physiol 49:335–347 Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J et al (2004) Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29(10):1326–1334 Benedict C, Kern W, Schultes B, Born J, Hallschmid M (2008) Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J Clin Endocrinol Metab 93(4):1339–1344 Bennecib M, Gong CX, Grundke-Iqbal I, Iqbal K (2000) Role of protein phosphatase-2A and-1 in the regulation of GSK-3, cdk 5 and cdc 2 and the phosphorylation of tau in rat forebrain. FEBS Lett 485:87–93 Bhat RV, Shanley J, Correll MP, Fieles WE, Keith RA, Scott CW, Lee CM (2000) Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3b in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci USA 97:11074–11079 Blass JP, Gibson GE, Hoyer S (2002) The role of the metabolic lesion in Alzheimer’s disease. J Alzheimer’s Dis 4:225–232 Buckner RL, Sepulcre J, Talukdar T, Krienen FM, Liu H, Hedden T et al (2009) Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer’s disease. J Neurosci 29(6):1860–1873 Chang YT, Chang WN, Tsai NW, Huang CC, Kung CT, Su YJ, Lin WC, Cheng BC, Su CM, Chiang YF, Lu CH (2014) The roles of

The metabolism hypothesis of AD biomarkers of oxidative stress and antioxidant in Alzheimer’s disease: a systematic review. Biomed Res Int 2014:182303 Chiu SL, Chen CM, Cline HT (2008) Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 58(5):708–719 Cohen P, Frame S (2001) The renaissance of GSK. 3. Nat Rev Mol Cell Biol 2:769–776 Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A et al (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69(1):29–38 Craft S, Cholerton B, Baker LD (2013) Insulin and Alzheimer’s disease: untangling the web. J Alzheimers Dis 33(Suppl 1):S263–S275 Cross DAE, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated protein kinase. Nature 378:785–789 Cross DA, Watt PW, Shaw M, von der Kaay J, Downes CP, Holder JC, Cohen P (1997) Insulin activates protein kinase B, inhibits glycogen synthase kinase-3 and activates glycogen synthase by rapamycin-sensitive pathways in skeletal muscle and adipose tissue. FEBS Lett 406:211–215 De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP et al (2009) Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA 106(6):1971–1976 de Haan W, Mott K, van Straaten EC, Scheltens P, Stam CJ (2012) Activity dependent degeneration explains hub vulnerability in Alzheimer’s disease. PLoS Comput Biol 8(8):e1002582 de Quervain DJF, Poirier R, Wollmer MA, Grimaldi LME, Tsolaki M, Streffer JR, Hock C, Nitsch RM, Mohajeri MH, Papassotiropoulos A (2004) Glucocorticoid-related genetic susceptibility for Alzheimer’s disease. Human Mol Genet 13:47–52 Duax WL, Griffin JF, Ghosh D (1996) The fascinating complexities of steroid-binding enzymes. Curr Opin Struct Biol 6:813–823 Fang X, Yu SX, Lu Y, Bast RC Jr, Woodgett JR, Mills GB (2000) Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci USA 97: 11960–11965 Freiherr J, Hallschmid M, Frey WH 2nd, Brunner YF, Chapman CD, Holscher C et al (2013) Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs 27(7):505–514 Fro¨lich LD, Blum-Degen H-G, Bernstein S, Engelsberger J, Humrich S, Laufer D, Muschner A, Thalheimer A, Tu¨rk S, Hoyer P, Riederer (1998) Insulin and insulin receptors in the brain in aging and in sporadic Alzheimer’s disease. J Neural Transm 105:423–438 Fro¨lich L, Blum-Degen D, Riederer P, Hoyer S (1999) A disturbance of the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease. Ann NY Acad Sci 893:290–294 Fro¨lich L, Go¨tz ME, Weinmu¨ller M, Youdim MB, Barth N, Dirr A, Gsell W, Jellinger K, Beckmann H, Riederer P (2004) (r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia. J Neural Transm 111:295–310 Gru¨nblatt E, Bartl J, Riederer P (2011) The link between iron, metabolic syndrome, and Alzheimer’s disease. J Neural Transm 118(3):371–379 Hager K, Marahrens A, Kenklies M, Riederer P, Mu¨nch G (2001) Alpha-lipoic acid as a new treatment option for Alzheimer type dementia. Arch Gerontol Geriatr 32:275–282 Hardas SS, Sultana R, Clark AM, Beckett TL, Szweda LI, Murphy MP, Butterfield DA (2013) Oxidative modification of lipoic acid by HNE in Alzheimer disease brain. Redox Biol 1:80–85

Havrankova J, Roth J, Brownstein M (1978) Insulin receptors are widely distributed in the central nervous system of the rat. Nature 272(5656):827–829 Henneberg N, Hoyer S (1994) Short-term or long-term intracerebroventricular (i.c.v.) infusion of insulin exhibits a discrete anabolic effect on cerebral energy metabolism in the rat. Neurosci Lett 175:153–156 Holmquist L, Stuchbury G, Berbaum K, Muscat S, Young S, Hager K, Engel J, Mu¨nch G (2007) Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias. Pharmacol Ther 113(1):154–164 Hoyer S (2002) The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. J Neural Transm 109:341–360 Hoyer S, Fro¨lich L (2007) Chapter XI: Brain insulin function and insulin signal transduction in sporadic Alzheimer disease. In: Sun M-K (ed) Research progress in Alzheimer’s disease and dementias. Nova Science, New York, pp 205–255. ISBN 1-59454-949-4 Hoyer S, Oesterreich K, Wagner O (1988) Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type? J Neurol 235:143–148 Hoyer S, Nitsch R, Oesterreich K (1991) Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer-type: a cross-sectional comparison against advanced late-onset dementia and incipient early-onset cases. J Neural Transm (PD-Sect) 3:1–14 Hoyer S, Prem L, Sorbi S, Amaducci L (1993) Stimulation of glycolytic key enzymes in cerebral cortex by insulin. NeuroReport 4:991–993 Hughes K, Nikolakaki E, Plyte SE, Totty NF, Woodgett JR (1993) Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J 12:803–808 Jellinck PH, Pavlides C, Sakai RR, McEwen BS (1999) 11bhydroxysteroid dehydrogenase functions reversibly as an oxidoreductase in the rat hippocampus in vivo. J Steroid Biochem Mol Biol 71:139–144 Joseph J, Shukitt-Hale B, Denisova NA, Martin A, Perry G, Smith MA (2001) Copernicus revisited: amyloid beta in Alzheimer’s disease. Neurobiol Aging 22:131–146 Ko LW, Sheu KF, Thaler HT, Markesbery WR, Blass JP (2001) Selective loss of KGDHC-enriched neurons in Alzheimer temporal cortex: does mitochondrial variation contribute to selective vulnerability? J Mol Neurosci 17:361–369 Kyriakis JM, Hausman RE, Peterson SW (1987) Insulin stimulates choline acetyltransferase activity in cultured embryonic chicken retina neurons. Proc Natl Acad Sci USA 84:7463–7467 Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alz-heimer’s disease. Nat Genet 45(12):1452–1458 Lee S, Tong M, Hang S, Deochand C, de la Monte S (2013) CSF and brain indices of insulin resistance, oxidative stress and neuroinflammation in early versus late Alzheimer’s disease. J Alzheimers Dis Parkinsonism 3:128 Li M, Wang X, Meintzer M, Laessig T, Birnbaum MJ, Heidenreich KA (2000) Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3b. Mol Cell Biol 20:9356–9363 Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ et al (2009) Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci 29(28):9078–9089 Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, Carlson DA, Mu¨nch G (2008) Lipoic acid as an anti-

123

K. Morgen, L. Fro¨lich inflammatory and neuroprotective treatment for Alzheimer’s disease. Adv Drug Deliv Rev 60:1463–1470 Malenka RC (1994) Synaptic plasticity in the hippocampus: LTP and LTD. Cell 78(4):535–538 Manolopoulos KN, Klotz LO, Korsten P, Bornstein SR, Barthel A (2010) Linking Alzheimer’s disease to insulin resistance: the FoxO response to oxidative stress. Mol Psychiatry 15(11):1046–1052 Marcello E, Epis R, Saraceno C, Di Luca M (2012) Synaptic dysfunction in Alzheimer’s disease. Adv Exp Med Biol 970:573–601 Marks JL, Porte D Jr, Stahl WL, Baskin DG (1990) Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127(6):3234–3236 Plum L, Schubert M, Bruning JC (2005) The role of insulin receptor signaling in the brain. Trends Endocrinol Metab 16(2):59–65 Pratico` D (2008) Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol Sci 29(12):609–615 Ramakrishna S, Benjamin WB (1998) Insulin action rapidly decreases multifunctional protein kinase activity in rat adipose tissue. J Biol Chem 263:12677–12681 Reger MA, Craft S (2006) Intranasal insulin administration: a method for dissociating central and peripheral effects of insulin. Drugs Today (Barc) 42(11):729–739 Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA et al (2008) Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 13(3):323–331 Rinaudo MT, Curto M, Bruno R, Marino C, Rossetti V, Mostert M (1987) Evidence of an insulin generated pyruvate dehydrogenase stimulating factor in rat brain plasma membranes. Ital J Biochem 19:909–913 Schechter R, Whitmire J, Holtzclaw L, George M, Harlow R, Devaskar SU (1992) Developmental regulation of insulin in the mammalian central nervous system. Brain Res 582(1):27–37 Schechter R, Beju D, Gaffney T, Schaefer F, Whetsell L (1996) Preproinsulin I and II mRNAs and insulin electron microscopic immunoreaction are present within the rat fetal nervous system. Brain Res 736(1–2):16–27 Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27(10):1372–1384 Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D et al (2004) Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci USA 101(9):3100–3105

123

Seckl JR, Walker BR (2001) Minireview: 11b-hydroxysteroid dehydrogenase type 1-a tissue-specific amplifier of glucocorticoid action. Endocrinology 142:1371–1376 Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791 Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842 Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T (2012) Effect of intranasal insulin on cognitive function: a systematic review. J Clin Endocrinol Metab 97(2):366–376 Shinto L, Quinn J, Montine T, Dodge HH, Woodward W, BaldaufWagner S, Waichunas D, Bumgarner L, Bourdette D, Silbert L, Kaye J (2014) A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease. J Alzheimers Dis 38(1):111–120 Stockhorst U, de Fries D, Steingrueber HJ, Scherbaum WA (2004) Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans. Physiol Behav 83(1):47–54 Stockhorst U, de Fries D, Steingrueber HJ, Scherbaum WA (2011) Unconditioned and conditioned effects of intranasally administered insulin vs placebo in healthy men: a randomised controlled trial. Diabetologia 54(6):1502–1506 Supekar K, Menon V, Rubin D, Musen M, Greicius MD (2008) Network analysis of intrinsic functional brain connectivity in Alzheimer’s disease. PLoS Comput Biol 4(6):e1000100 Sutherland C, Cohen P (1994) The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p 70S6 kinase or MAP kinase-activated protein kinase-1 in vitro. FEBS Lett 338:37–42 Sweeney G, Klip A (1998) Regulation of the Na?/K?-ATPase by insulin: Why and how? Mol Cell Biochem 182:121–133 Vanhaesebroeck A, Alessi DR (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346:561–576 Wadman M (2012) US government sets out Alzheimer’s plan. Nature 485(7399):426–427 Welsh GI, Proud CG (1993) Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor elF-2B. Biochem J 294:625–629