Clinica Chimica Acta 444 (2015) 18–23

Contents lists available at ScienceDirect

Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim

Invited critical review

Insulin resistance and cognitive dysfunction Lina Ma, Jieyu Wang, Yun Li ⁎ Department of Geriatrics, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China

a r t i c l e

i n f o

Article history: Received 24 December 2014 Received in revised form 25 January 2015 Accepted 27 January 2015 Available online 4 February 2015 Keywords: Insulin resistance Mild cognitive impairment Insulin Alzheimer's disease

a b s t r a c t Epidemiologic and biologic studies support a link between type 2 diabetes mellitus and Alzheimer's disease, but the precise mechanism linking the two remains unclear. Growing evidence supports the concept that insulin resistance is important in the pathogenesis of cognitive impairment and neurodegeneration. Insulin plays a profound role in cognitive function. Impaired insulin signaling in the advancement of cognitive dysfunction is relevant to the pathophysiologic mechanisms of cognitive impairment. In this paper we discuss the relationship between insulin resistance and cognitive impairment and review potential mechanisms of this disease process. Evidence, to date, suggests that brain insulin resistance is an independent risk factor for cognitive impairment. © 2015 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Physiological functions and secretion regulation of insulin . . . . . . 2.2. The role of insulin in the nervous system . . . . . . . . . . . . . . 2.3. The role of insulin resistance in the nervous system . . . . . . . . . 3. Insulin resistance and cognitive impairment . . . . . . . . . . . . . . . . 3.1. Insulin resistance is an important risk factor for cognitive impairment . 3.2. Insulin can improve cognitive dysfunction caused by insulin resistance 4. Mechanisms of insulin resistance on cognitive impairment . . . . . . . . . 4.1. Insulin resistance prominently affects hippocampal plasticity . . . . . 4.2. Insulin resistance affects APP metabolism . . . . . . . . . . . . . . 4.3. Insulin resistance increases tau protein concentration . . . . . . . . 4.4. Insulin resistance affects brain inflammatory reaction . . . . . . . . 4.5. Insulin resistance and the ApoE ε4 allele . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Epidemiologic and biologic evidence supports a link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), ie, those with

⁎ Corresponding author at: Department of Geriatrics, Xuan Wu Hospital, Capital Medical University, #45 Changchun Street, Xicheng District, Beijing 100053, China. Tel./fax: +86 10 83198707. E-mail address: [email protected] (Y. Li).

http://dx.doi.org/10.1016/j.cca.2015.01.027 0009-8981/© 2015 Elsevier B.V. All rights reserved.

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

18 19 19 19 19 19 19 19 20 20 20 20 20 21 21 21 21 21

T2DM have a higher incidence of cognitive decline [1]. The prevalence of both T2DM and AD increases with age, and both diseases are chronic and are the leading causes of morbidity and mortality. Mild cognitive impairment (MCI) is a state between normal aging and AD. The MCI conversion rate to AD is high [2], and there is a high risk of MCI developing into dementia. Moreover, the incidence of MCI increases to 32.7% in diabetic patients [3]. The precise mechanism linking T2DM and cognitive impairment remains to be found out. Growing evidence supports the concept that insulin resistance (IR) plays an important role in the pathogenesis of cognitive impairment and neurodegeneration [1].

L. Ma et al. / Clinica Chimica Acta 444 (2015) 18–23

Glucose is an important energy source for the brain and subsequent insulin release from neuronal vesicles. Insulin is an active substance that can affect neurons in the brain and periphery, and has multiple biological functions including regulation of blood glucose and energy metabolism. Research has shown that brain insulin plays an important role in cognitive activities (such as learning and memory) in elderly people [4], in addition to metabolic and feeding effects, promoting nerve cell growth and development, and regulation of neurotransmitter release. Advanced age, low education degree, hypertension, hyperlipidemia, heart disease, diabetes, transient ischemic attack, smoking, drinking, and apolipoprotein E (ApoE) 4 allele polymorphism have all been shown to be risk factors for MCI development [5–7]. Vascular risk factors play an important role in MCI pathogenesis, and early and effective control of vascular risk factors of cognitive function can reduce the incidence rate of cognitive function decline and dementia in old age [8,9]. There is convincing epidemiological evidence showing an increased risk of dementia in people with diabetes, but there are few mechanistic studies that provide a clear pathophysiological link, although the cause may be multifactorial [1]. IR is an independent risk factor for MCI, and in the brain, may be associated with sporadic Alzheimer's disease [10,11]. Dementia prevalence is increasing with rapid aging in the population, and MCI as an intervention stage to prevent dementia has become a research hotspot [12,13]. Most recent studies have focused on the role of IR as possible links between diabetes and AD, and the disturbances in brain insulin signaling mechanisms may contribute to the molecular, biochemical, and histopathological lesions in AD [1,14]. Therefore, in this paper, how IR and cognitive impairment are mutually linked and the possible mechanisms are discussed.

19

of insulin in brain extracts [30], the expression of insulin and insulin receptors are widely distributed in brain neurons and glial cells, especially in the cerebral cortex, hippocampus, hypothalamus, and olfactory bulb [31], all areas closely related with cognition. Insulin-sensitive glucose carriers are found in these areas, and can enhance the insulin signal, increase brain glucose use, and regulate learning and memory [32]. Insulin receptor mRNA is located in neuronal cell bodies, with receptor protein distributed in pyramidal cell axons, hypothalamic-adrenergic neuronal terminals, CA1 region of the hippocampus, and membrane surface of synaptosomal branches in the rat olfactory bulb [33–35]. High concentrations of insulin receptor are found in the thalamus, caudate–putamen, and some mesencephalic and brainstem nuclei during neurogenesis, but these same areas have a low insulin receptor density in adult rat brains, which indicates that insulin receptor density between the embryonic and adult brain has a significant difference [36]. 2.3. The role of insulin resistance in the nervous system

2. Insulin resistance

IR refers to reduced sensitivity of insulin on target organs, and is a characteristic metabolic defect that coexists with hyperinsulinemia. Long-term hyperinsulinemia can damage blood brain barrier function and insulin activity [37]. IR causes long-term neuronal exposure to a high level insulin environment, leading to neuronal degeneration and causing irreversible memory impairment [38,39]. IR in the peripheral tissues facilitates IR in the brain by reducing brain insulin uptake and increasing levels of beta amyloid (Aβ) [40]. AD incidence in late diabetic patients is two times higher compared with normal elderly people [41], and thought to arise from islet β cell dysfunction that causes impaired insulin secretion and resistance, leading to nervous system damage and ultimately influencing cognitive function in patients [41].

2.1. Physiological functions and secretion regulation of insulin

3. Insulin resistance and cognitive impairment

Insulin is a small molecule protein composed of 51 amino acid residues arranged into an A chain of 21 peptides and B chain of 30 peptides that are linked by two disulfides and has a molecular weight of 5808 Da [15]. The metabolic effect of insulin is predominantly regulated by binding to various insulin receptors [16]. Insulin receptor was located and quantified in the central nervosa system in 1978 [17,18]. Signal transduction post-receptor binding commonly involves the insulin receptor substrate (IRS), with IRS-1 and IRS-2 present in muscle, fat, and islet B cells, and IRS-3 in brain tissue [19–21]. IRS phosphorylation by a variety of protein kinases and phosphatases via the anchoring domain and activation site, and link proteins to phospholipase and ion channel facilitation factors mediate downstream reactions. Insulin regulates metabolism and maintains balance in energy function within the body.

AD and diabetic mellitus have a shared pathogenesis in IR. Diabetes transmits peripheral insulin resistance to the central nervous system through the “liver brain axis”, which promotes cognitive dysfunction [42].

2.2. The role of insulin in the nervous system The role of insulin is best known in peripheral glucose homeostasis, and insulin signaling in the brain received less attention in the past decades. Nowadays, the function of insulin, the insulin-like growth factors (IGF) and their receptors in central nervous system has been a live topic [22]. The presence of insulin in the brain was first detected in 1978 [23], then high concentrations of insulin were reported not only in the human brain but also in several experimental animals [24]. IRS distribution is concomitant with insulin receptors in the brain [25]. Insulin and insulin receptors in nerve tissue stimulate release of a variety of enzymes involved in glucose metabolism, including choline acetyltransferase (ChAT). An important brain function of insulin is regulation of learning and memory [26]. Insulin not only regulates energy metabolism, but also provides nutritional support to nerve cells [27]. Brain insulin is obtained mainly from islet β cell secretion, and crosses the blood brain barrier via insulin receptor mediated transport [28], thereby regulating brain glucose. Insulin function in the brain is related to insulin receptor distribution [29]. Recent findings show a high concentration

3.1. Insulin resistance is an important risk factor for cognitive impairment Brain insulin deficiency and plasma insulin resistance may promote cognitive dysfunction. Central obesity is highly correlated with impaired cognitive function in the elderly [43]. Moreover, cognitive function in patients with metabolic syndrome was lower than a control group, and incidence of cognitive impairment significantly higher than controls over 6-month and 1-year periods [44]. IR promotes development of MCI and AD [45]. Studies have found that AD patients have low insulin levels in the brain and cerebrospinal fluid (CSF), and high insulin levels in plasma, which is related with impaired insulin signal transduction [46–48]. High levels of circulating insulin may be the consequence of insulin resistance, while the reduction in CSF insulin may be related to a decrease in insulin clearance and/or to a reduction in insulin uptake from a peripheral source through the blood brain barrier [46–48]. In addition, the expression mRNA and protein levels of insulin and IGF1 and the downstream signaling elements in the brain of AD patients are decreased [47]. An aberrant decline in IGF1 values was also suggested to play a role in the development of AD [22]. 3.2. Insulin can improve cognitive dysfunction caused by insulin resistance Deregulation of brain insulin signaling plays an important role in the development of AD. IR promotes development of cognitive dysfunction by hyperinsulinemia and impaired insulin signaling; therefore determining if insulin or insulin sensitizing agents are neuroprotective has become a research hotspot. Insulin is an important long-term neuroprotectant, and severe lack of it leads to neurodegeneration [49].

20

L. Ma et al. / Clinica Chimica Acta 444 (2015) 18–23

The brain insulin signaling pathway also offers a promising therapeutic target for treating AD [50]. Intrahippocampal insulin injection in normal rats significantly improves spatial memory ability [51]. In addition, nasal insulin in a diabetic mouse model had no effect on serum glucose levels, but improved diabetic related decline in cognitive function and changes in brain morphology and molecular pathology [52]. Long-term high fructose diets induce peripheral and central IR in rats, whereas glycine improves IR and cognitive impairment induced by fructose diets [53]. The above data indicates that insulin may be an attractive tool for neuroprotection against apoptosis, oxidative stress, Aβ toxicity, and brain ischemia [54]. A further study found that the insulin sensitizer, pioglitazone, improves decreased learning and memory function in a rat IR model, possibly by promoting expression of neuronal ChAT and insulin like growth factor-1, which maintain normal cholinergic nerve function [55]. Insulin administered to AD patients to keep glycemic levels constant can also improve memory formation [56]. A study has found that the systemic administration to healthy humans of insulin under euglycemic hyperinsulinemic conditions emerged a significant improvement in memory [57]. 4. Mechanisms of insulin resistance on cognitive impairment Typical AD pathological features include formation of neurofibrillary tangles and senile plaques, which are due to increased Aβ aggregation in the brain, and neuronal loss due to abnormal tau protein phosphorylation. Insulin reduces Aβ generation and aggregation, while the insulin degrading enzyme (IDE) degrades Aβ [58]. IR may be the initial factor for cognitive dysfunction, but the underlying mechanism is still unclear. Mechanisms suggested from the literature include: IR prominently affects hippocampal plasticity, altered amyloid precursor protein (APP) metabolism, elevated tau protein concentration, altered brain inflammatory reaction, and ApoE ε4 allele involvement [59].

AD. Aβ is the most important component of senile plaques, and a feature of AD pathology. Insulin directly influences APP metabolism, promotes α-secretase (with resulting cleavage of APP molecules), and transforms APP into soluble APPa (sAPPa). Insulin accelerates APP/Aβ agglomeration via tyrosine kinase receptor regulation and the mitogen activated protein kinase K pathway. In addition, insulin regulates Aβ levels by promoting Aβ transport to the neuronal gap and preventing Aβ degradation [67]. Hippocampal Aβ40 expression is significantly increased and escape latency period prolonged in IR rats, indicating that IR damages cognitive function due to increased Aβ protein expression [68]. Tau protein phosphorylation was also significantly enhanced in the IR model induced by fructose [69]. In AD transgenic mice, IR induced by diet promotes brain Aβ formation [70]. IDE is the main enzyme for Aβ degradation, and also responsible for insulin degradation. Affinity of IDE for insulin is higher than for Aβ. With high insulin levels, Aβ competes for IDE resulting in increased Aβ deposition [71]. Exposure to low levels of Aβ can upregulate IDE, which indicates that IDE may be an important therapeutic target because of its role in the degradation of Aβ and other substances [72]. Some data show that the activation of insulin signaling in the central nervous system can upregulate IDE activity, and may correct the IDE defects present in AD [73]. Insulin can prevent the formation of Aβ fibrils, stimulate the internalization of Aβ oligomers and inhibit their binding to neurons, and thereby protect synapses against Aβ oligomers [74]. In IR situation, the protective role of insulin against Aβ accumulation is reduced, and Aβ deposits downregulates the expression of insulin, then Aβ peptides inhibit the binding of insulin to its receptors, reduce receptor autophosphorylation, and finally impair insulin-induced signaling pathways [75]. Both brain insulin and IGF1 resistance are considered an early and common feature of AD, which seem to be closely associated with the IRS-I dysfunction triggered by Aβ oligomers that promote cognitive decline [76]. 4.3. Insulin resistance increases tau protein concentration

4.1. Insulin resistance prominently affects hippocampal plasticity Synaptic plasticity underlies higher brain functions such as learning and memory. Insulin affects hippocampal synaptic plasticity, and therefore has an effect on learning and memory. Insulin is beneficial to memory, and abnormal activity in the insulin signal transduction pathway impairs cognitive impairment [60]. Insulin modulates glutamatergic neurotransmission at the synapses and induces the longterm depression (LTD) process by decreasing the amount of α-amino3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in the post-synaptic membrane [61]. Increased insulin levels induce long-term potentiation (LTP) [62]. Insulin affects learning and memory through γ-aminobutyric acid (GABA) receptors by stimulating the translocation of these receptors to the plasma membrane and increases the functional GABA receptor expression on the post-synaptic and dendritic membranes of the neurons, which can be abolished by the action of a PI3K inhibitor [30,63]. Spatial memory ability and hippocampal synaptic plasticity are significantly decreased in a type 1 diabetes mellitus model induced by streptozotocin, but can be significantly corrected by early administration of insulin treatment [64]. IGF1 increases the synaptic transmission in the rat hippocampus through a mechanism in which AMPA receptors and PI3K activity are involved [65]. High fat diet is associated with telencephalic insulin resistance; it leads to failed activation of Akt/mTOR/GSK3β pathways by insulin in cortex and is associated with decreased postsynapticdensity-95 and dendritic spine density, and finally impairs spatial working memory in mice [66]. 4.2. Insulin resistance affects APP metabolism APP is present as a single gene on chromosome 21, which encodes a number of variants. Factors affecting APP metabolism include phospholipid C activation, phosphorylation, and the cholinergic system. Microtubule associated tau protein promotes neurofibrillary tangle formation in

Tau protein phosphorylation is due to regulation of protein kinases and phosphatases, with glycogen synthase kinase-3 beta (GSK-3β) and mitogen-activated protein kinase inducing phosphorylation [77]. Neurofibrillary tangles play an important role in AD pathology, and they are mainly composed of hyperphosphorylated tau molecules [78, 79]. In MCI patients complicated by IR, CSF tau protein levels are high [80]. IR in the central nervous system increases GSK-3β activity, and promotes tau protein phosphorylation [81]. In IR rats, prolonged escape latency periods, increased IR index, decreased ChAT activity, and increased APP and Aβ42 average optical density values were reported. Presenilin 1 (PS-1), β-site-APP cleavage enzyme-1 (BACE-1), and phosphorylated tau protein expression were also increased in brain, suggesting that IR causes impaired cognitive function, with its extent related to ChAT activity, and increased Aβ generation by regulating BACE1 and PS1 activity, while increased expression of phosphorylated tau protein may lead to AD disease [82]. 4.4. Insulin resistance affects brain inflammatory reaction The inflammatory reaction is a core pathological mechanism of AD [83–85]. Inflammatory responses, which are present in obesity and T2DM, are closely related to the development of IR in both peripheral and central tissues, thus may increase the risk of AD [86]. Inflammatory factors such as interleukin-1, interleukin-6 (IL-6), and tumor necrosis factor alpha are increased in brain tissue from AD patients [87], indicating the presence of a nonspecific immune inflammatory reaction in the early phase of brain plaque formation [88–91]. AD incidence is low in a patient population receiving non-steroidal anti-inflammatory drugs [92]. These studies indicate that the inflammatory reaction plays an important role in AD development. Microglial cells (MG) comprise the brain's cellular immune response, and play a neuroprotective role though phagocytosis of pathogenic microorganisms and harmful

L. Ma et al. / Clinica Chimica Acta 444 (2015) 18–23

particles in brain tissue. However, MG can also be activated into reactive MG by inflammatory factors, with secretory cytokines leading to neuronal injury and apoptosis. IR affects the brain inflammatory response mediated by MG and astrocytes involved in AD pathology, increases plasma insulin reactivity, decreases insulin sensitivity, and activates brain proinflammatory cytokines such as C reactive protein and IL-6 [92]. Increased levels of inflammatory cytokines can also impair spatial learning by working on hippocampal synaptic plasticity [93]. PI3K/Akt/GSK-3 pathway plays an important role in controlling inflammation [94]. PI3K pathway has a negative effect on IL-12 [95], GSK-3β activity is increased in both T2DM and AD, and this process enables it to phosphorylate the IR and IRS-1, which decrease the phosphorylation of tyrosine residues of the IR and IRS-1 [96].

21

begin to fail in the early stages of neurodegeneration [111], so further studies are needed to clarify the benefits and limitations of intranasal insulin medication. In the clinic, doctors should heed IR development, while strengthening management in patients with diseases such as metabolic syndrome, obesity, hypertension, and diabetes by assessing cognitive function, as timely discovery and early intervention may prevent cognitive dysfunction and AD development. Conflicts of interest None declared. Acknowledgments

4.5. Insulin resistance and the ApoE ε4 allele ApoE is a polymorphic protein with common variants known as E2, E3, and E4 that are encoded by the ε2, ε3, and ε4 alleles, respectively, with population frequencies of approximately 8, 77 and 15%, respectively [97–99]. ApoE4 has been confirmed as an important factor for dementia and progress of cognitive impairment in the elderly [100,101]. ApoE protein, Aβ, and tau protein interact in a specific way, which may be the biological basis for ApoE effect on dementia development [102]. The ApoE ε4 allele polymorphism is an independent risk factor for MCI, and cognitive level in ε4 carriers is lower than noncarriers [103]. ApoE ε4 incidence in MCI patients is significantly higher than the normal population [103]. Risk ratio of late-onset AD in ApoE ε4 carriers is approximately three times higher than noncarriers [104]. Hippocampal ChAT activity is decreased in AD patients, and ChAT activity in ApoE ε4 noncarrier AD patients is close to normal age-matched controls, suggesting that ApoE ε4 plays a role in AD cholinergic dysfunction [105]. After adjusting for age, occupation, smoking, drinking, and cardiovascular disease, incidence rate of cognitive impairment in ε4 allele carriers is higher than noncarriers. Moreover, risk of progressive cognitive impairment is higher and declines in cognitive function over three years more common in ε4 homozygous carriers [105]. Age of dementia onset decreases with increasing amount of E4 alleles, and AD onset age in E4 noncarriers is older (e.g. 85 years old) while dementia onset age is younger (e.g. 75 years old) in homozygous E4 patients [105]. The ApoE ε4 allele frequency in IR patients is significantly higher than controls, with IR index and ApoE ε4 gene positively correlated, suggesting that IR is related to MCI and ApoE ε4, and that IR and ApoE ε4 have clinical application in predicting MCI occurrence and transformation into AD [106]. 5. Conclusion Although secreted peripherally, insulin also plays a profound role in cognitive function, and IR facilitates the brain's susceptibility to neurodegeneration [107]. Certain insulin actions are different in the central nervous system, such as hormone-induced glucose uptake due to a low insulin-sensitive glucose transporter-4 (GLUT-4) activity, and because of the predominant presence of GLUT-1 and GLUT-3 [108]. Increasing evidence suggests that insulin signaling in the brain is necessary to maintain health of neuronal cells, promote learning and memory, decrease oxidative stress, and ultimately increase neuronal survival [109]. IR is closely related to occurrence and development of cognitive dysfunction. The role of impaired insulin signaling in the advancement of cognitive dysfunction is relevant to the pathophysiological mechanisms of cognitive impairment [109,110]. Therefore, brain insulin resistance is an important and early abnormality in AD, and that increasing brain supply and utilization of insulin improves cognition and memory. A review emphasis on discussing outcomes of clinical trials and interpreting discordant results has found that intranasal insulin therapy can efficiently and directly target the brain to support energy metabolism, myelin maintenance, cell survival and neuronal plasticity, which

This work was supported by grants from the Ministry of Education in China Project of Humanities and Social Sciences (12YJCZH146), and Beijing Municipal Health Bureau Research Fund (Jing 13-02). References [1] Barbagallo M, Dominguez LJ. Type 2 diabetes mellitus and Alzheimer's disease. World J Diabetes 2014;5:889–93. [2] Younes L, Albert M, Miller MI, et al. Inferring changepoint times of medial temporal lobe morphometric change in preclinical Alzheimer's disease. Neuroimage Clin 2014;5:178–87. [3] Zhao X, Tan Y, Bao J, et al. Clinical observation on relationship between insulin resistance and mild cognitive impairment. Stroke Nerv Dis 2009;16:155–8. [4] Park SJ, Chung YH, Lee JH, et al. Growth hormone-releaser diet attenuates cognitive dysfunction in klotho mutant mice via insulin-like growth factor-1 receptor activation in a genetic aging model. Endocrinol Metab (Seoul) 2014;29:336–48. [5] Tokuchi R, Hishikawa N, Kurata T, et al. Clinical and demographic predictors of mild cognitive impairment for converting to Alzheimer's disease and reverting to normal cognition. J Neurol Sci 2014 [Epub ahead of print]. [6] Haj-Hassan S, Hohman T, Liu D, et al. A-28 vascular risk and cognitive decline in older adults with and without mild cognitive impairment (MCI). Arch Clin Neuropsychol 2014;29:513. [7] Cuesta P, Garcés P, Castellanos NP, et al. Influence of the APOE ε4 allele and mild cognitive impairment diagnosis in the disruption of the MEG resting state functional connectivity in sources space. J Alzheimers Dis 2014 [Epub ahead of print]. [8] O'Brien JT, Markus HS. Vascular risk factors and Alzheimer's disease. BMC Med 2014;12:218. [9] Casado Naranjo I, Portilla Cuenca JC, Duque de San Juan B, et al. Association of vascular factors and amnestic mild cognitive impairment: a comprehensive approach. J Alzheimers Dis 2014 [Epub ahead of print]. [10] Sasaoka T, Wada T, Tsuneki H. Insulin resistance and cognitive function. Nihon Rinsho 2014;72:633–40. [11] Ma L, Feng M, Qian Y, et al. Insulin resistance is an important risk factor for cognitive impairment in elderly patients with primary hypertension. Yonsei Med J 2015; 56:89–94. [12] Lim ML, Gomez R, Koopman C. A review of amnestic MCI screening in east/southeast Asian older adults with low education: implications for early informant-clinician collaboration. Int J Geriatr Psychiatry 2014 [Epub ahead of print]. [13] Davey DA. Alzheimer's disease and vascular dementia: one potentially preventable and modifiable disease? Part II: Management, prevention and future perspective. Neurodegener Dis Manag 2014;4(3):261–70. [14] Ma L, Zhao Z, Wang R, et al. Caloric restriction can improve learning ability in C57/ BL mice via regulation of the insulin-PI3K/Akt signaling pathway. Neurol Sci 2014; 35:1381–6. [15] Cannon CE, Titchenell PM, Groff DN, et al. The Polycomb protein, Bmi1, regulates insulin sensitivity. Mol Metab 2014;3(8):794–802. [16] Ma H, Ma J, Xue P, Gao Y, Li Y. Osteoblast proliferation is enhanced upon the insulin receptor substrate 1 overexpression via PI3K signaling leading to down-regulation of NFκB and BAX pathway. Exp Clin Endocrinol Diabetes 2014 [Epub ahead of print]. [17] Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 1978;272(5656):827–9. [18] Lowe Jr WL, Boyd FT, Clarke DW, Raizada MK, Hart C, LeRoith D. Development of brain insulin receptors: structural and functional studies of insulin receptors from whole brain and primary cell cultures. Endocrinology 1986;119(1):25–35. [19] Jiang Y, Biswas SK, Steinle JJ. Serine 307 on insulin receptor substrate 1 is required for SOCS3 and TNF-α signaling in the rMC-1 cell line. Mol Vis 2014;20:1463–70. [20] Kapogiannis D, Boxer A, Schwartz JB, et al. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. FASEB J 2014 [Epub ahead of print]. [21] Luo J, Wen Q, Li J, et al. Increased expression of IRS-1 is associated with lymph node metastasis in nasopharyngeal carcinoma. Int J Clin Exp Pathol 2014;7(9):6117–24. [22] Werner H, Leroith D. Insulin and insulin-like growth factor receptors in the brain: physiological and pathological aspects. Eur Neuropsychopharmacol 2014;24(12): 1947–53.

22

L. Ma et al. / Clinica Chimica Acta 444 (2015) 18–23

[23] Havrankova J, Schmechel D, Roth J, Brownstein M. Identification of insulin in rat brain. Proc Natl Acad Sci U S A 1978;75(11):5737–41. [24] Dorn A, Bernstein HG, Rinne A, Ziegler M, Hahn HJ, Ansorge S. Insulin and glucagonlike peptides in the brain. Anat Rec 1983;207(1):69–77. [25] Long-Smith CM, Manning S, McClean PL, et al. The diabetes drug liraglutide ameliorates aberrant insulin receptor localisation and signalling in parallel with decreasing both amyloid-β plaque and glial pathology in a mouse model of Alzheimer's disease. Neuromolecular Med 2013;15(1):102–14. [26] Yang Y, Ma D, Wang Y, et al. Intranasal insulin ameliorates tau hyperphosphorylation in a rat model of type 2 diabetes. J Alzheimers Dis 2014; 33(2):329–38. [27] Brankatschk M, Dunst S, Nemetschke L, Eaton S. Delivery of circulating lipoproteins to specific neurons in the Drosophila brain regulates systemic insulin signaling. Elife 2014;2:3. [28] Spielman LJ, Little JP, Klegeris A. Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration. J Neuroimmunol 2014; 273(1–2):8–21. [29] Neumann KF, Rojo L, Navarrete LP, et al. Insulin resistance and Alzheimer's disease: molecular links and clinical implications. Curr Alzheimer Res 2008;5:438–47. [30] Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol 2013;47(1):145–71. [31] Santos GJ, Ferreira SM, Ortis F, et al. Metabolic memory of ß-cells controls insulin secretion and is mediated by CaMKII. Mol Metab 2014;3:484–9. [32] Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 2004;3:169–78. [33] Hami J, Kheradmand H, Haghir H. Sex differences and laterality of insulin receptor distribution in developing rat hippocampus: an immunohistochemical study. J Mol Neurosci 2014;54(1):100–8. [34] Agrawal R, Tyagi E, Shukla R, Nath C. Insulin receptor signaling in rat hippocampus: a study in STZ (ICV) induced memory deficit model. Eur Neuropsychopharmacol 2011;21(3):261–73. [35] Wang H, Wang R, Zhao Z, et al. Coexistences of insulin signaling-related proteins and choline acetyltransferase in neurons. Brain Res 2009;1249:237–43. [36] Kar S, Chabot JG, Quirion R. Quantitative autoradiographic localization of [125I] insulin-like growth factor I, [125I]insulin-like growth factor II, and [125I]insulin receptor binding sites in developing and adult rat brain. J Comp Neurol 1993; 333(3):375–97. [37] Tucsek Z, Toth P, Sosnowska D, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol A Biol Sci Med Sci 2014;69(10):1212–26. [38] Blázquez E, Velázquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease. Front Endocrinol (Lausanne) 2014;5:161. [39] Dineley KT, Jahrling JB, Denner L. Insulin resistance in Alzheimer's disease. Neurobiol Dis 2014 [Epub ahead of print]. [40] Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 2011; 68(1):51–7. [41] Wang F, Song YF, Yin J, et al. Spatial memory impairment is associated with hippocampal insulin signals in ovariectomized rats. PLoS One 2014;9:e104450. [42] Morris JK, Vidoni ED, Honea RA, et al. Impaired glycemia increases disease progression in mild cognitive impairment. Neurobiol Aging 2014;35:585–9. [43] Dahl Aslan AK, Starr JM, Pattie A, Deary I. Cognitive consequences of overweight and obesity in the ninth decade of life? Age Ageing 2014 [Epub ahead of print]. [44] Chen H. Study on correlation between syndrome and senile cognitive ability integrated metabolism. Jilin Med 2014;35(4):812–3. [45] Kim TE, Lee DH, Kim YJ, et al. The relationship between cognitive performance and insulin resistance in non-diabetic patients with mild cognitive impairment. Int J Geriatr Psychiatry 2014 [Epub ahead of print]. [46] Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes? Alzheimers Dis 2005;7:63–80. [47] Frolich L, Blum-Degen D, Riederer P, Hoyer S. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease. Ann N Y Acad Sci 1999;893:290–3. [48] Ghasemi R, Dargahi L, Haeri A, Moosavi M, Mohamed Z, Ahmadiani A. Brain insulin dysregulation: implication for neurological and neuropsychiatric disorders. Mol Neurobiol 2013;47(3):1045–65. [49] Evans MC, Rizwan MZ, Anderson GM. Insulin action on GABA neurons is a critical regulator of energy balance but not fertility in mice. Endocrinology 2014;155: 4368–79. [50] Chen Y, Deng Y, Zhang B, Gong C. Deregulation of brain insulin signaling in Alzheimer's disease. Neurosci Bull 2014;30(2):282–94. [51] McNay EC, Ong CT, McCrimmon RJ, et al. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem 2010;93:546–53. [52] Wang X, Zheng W, Xie JW, et al. Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol Neurodegener 2010;2:46. [53] Dong H, Han D, Xu R, et al. Effects of glycine on insulin resistance and cognitive impairment induced by high-fructose diet. Chin J Pathophysiol 2012;28(2):302–7. [54] Rasoul G, Ali H, Leila D, Zahurin M, Abolhassan A. Insulin in the brain: sources, localization and functions. Mol Neurobiol 2013;47(1):145–71.

[55] Liu X, Zheng M, Hao Y, et al. Study of the effects and mechanisms of plogliazone on cognition function and vigor of choline acetyltransferase in insulin resistance in rats. Stroke Nerv Dis 2009;16(2):75–8. [56] Kern W, Peters A, Fruehwald-Schultes B, Deininger E, Born J, Fehm HL. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology 2001; 74(4):270–80. [57] Ott V, Benedict C, Schultes B, Born J, Hallschmid M. Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism. Diabetes Obes Metab 2012;14(3):214–21. [58] Grasso G, Mielczarek P, Niedziolka M, Silberring J. Metabolism of cryptic peptides derived from neuropeptide FF precursors: the involvement of insulin-degrading enzyme. Int J Mol Sci 2014;15(9):16787–99. [59] Schrijvers EM, Witteman JC, Sijbrands EJ, et al. Insulin metabolism and the risk of Alzheimer disease: the Rotterdam Study. Neurology 2010;75:1982–7. [60] Feng B, Hu P, Lu SJ, et al. Effects of APP 5-mer peptide analogue P165 on the synaptic proteins and insulin signal transduction proteins. Int J Clin Exp Med 2014;7: 549–57. [61] Huang CC, Lee CC, Hsu KS. An investigation into signal transduction mechanisms involved in insulin-induced long-term depression in the CA1 region of the hippocampus. J Neurochem 2004;89(1):217–31. [62] Izumi Y, Yamada KA, Matsukawa M, et al. Effects of insulin on long-term potentiation in hippocampal slices from diabetic rats. Diabetologia 2003;46:1007–12. [63] Evans MC, Rizwan MZ, Anderson GM. Insulin action on GABA neurons is a critical regulator of energy balance but not fertility in mice. Endocrinology 2014; 155(11):4368–79. [64] Biessels GJ, Kamal A, Urban IJ, et al. Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res 1998;800:125–35. [65] Ramsey MM, Adams MM, Ariwodola OJ, Sonntag WE, Weiner JL. Functional characterization of des-IGF-1 action at excitatory synapses in the CA1 region of rat hippocampus. J Neurophysiol 2005;94(1):247–54. [66] Arnold SE, Lucki I, Brookshire BR, et al. High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiol Dis 2014;67:79–87. [67] Ghasemi R, Zarifkar A, Rastegar K, et al. Insulin protects against Aβ-induced spatial memory impairment, hippocampal apoptosis and MAPKs signaling disruption. Neuropharmacology 2014;85:113–20. [68] Lv A, Zhu S, Zhang X, et al. The effect of insulin resistance on hippocampus Aβ expression and cognitive behavior in rats. Chin Pract Neural Dis J 2011;14(21):40–1. [69] Mielke JG, Taghibiglou C, Liu L, et al. A biochemical and functional characterization of diet-induced brain insulin resistance. J Neurochem 2005;93:1568–78. [70] Ho L, Qin W, Pompl PN, et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J 2004;8:902–4. [71] Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 2003;100:4162–7. [72] Lynch JA, George AM, Eisenhauer PB, et al. Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures. J Neurosci Res 2006;83(7):1262–70. [73] Zhao L, Teter B, Morihara T, et al. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention. J Neurosci 2004;24(49):11120–6. [74] Rensink AA, Otte-Holler I, de Boer R, et al. Insulin inhibits amyloid beta-induced cell death in cultured human brain pericytes. Neurobiol Aging 2004;25(1):93–103. [75] Lee HK, Kumar P, Fu Q, Rosen KM, Querfurth HW. The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. Mol Biol Cell 2009;20(5):1533–44. [76] Talbot K, Wang HY, Kazi H, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 2012;122(4):1316–38. [77] Deres L, Bartha E, Palfi A, et al. PARP-inhibitor treatment prevents hypertension induced cardiac remodeling by favorable modulation of heat shock proteins, Akt-1/ GSK-3β and several PKC isoforms. PLoS One 2014;9(7):e102148. [78] Johnson GV. Tau phosphorylation and proteolysis: insights and perspectives. J Alzheimers Dis 2006;9:243–50. [79] Rissman RA, Poon WW, Blurton-Jones M, et al. Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 2004;114(1):121–30. [80] Kaiser E, Schönknecht P, Hunt A, Thomann PA, Pantel J, Schröder J. CSF levels of total tau protein in patients with mild cognitive impairment and Alzheimer's disease. Z Gerontol Geriatr 2008;41(6):497–501. [81] Sharma S, Taliyan R. Neuroprotective role of indirubin-3′-monoxime, a GSKβ inhibitor in high fat diet induced cognitive impairment in mice. Biochem Biophys Res Commun 2014;452(4):1009–15. [82] Yuan S, Gao S, Liu X, et al. The change of cognition function in insulin resistance rats and its brain tissues with Alzheimer-like disease. Stroke Nerv Dis 2010;17(3): 139–43. [83] Khan TK, Alkon DL. Peripheral biomarkers of Alzheimer's disease. J Alzheimers Dis 2014 [Epub ahead of print]. [84] Phillips EC, Croft CL, Kurbatskaya K, et al. Astrocytes and neuroinflammation in Alzheimer's disease. Biochem Soc Trans 2014;42(5):1321–5. [85] Terrill-Usery SE, Mohan MJ, Nichols MR. Amyloid-β(1-42) protofibrils stimulate a quantum of secreted IL-1β despite significant intracellular IL-1β accumulation in microglia. Biochim Biophys Acta 2014;1842(11):2276–85. [86] Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383–421. [87] Montine TJ, Kaye JA, Montine KS, McFarland L, Morrow JD, Quinn JF. Cerebrospinal fluid abeta42, tau, and f2-isoprostane concentrations in patients with Alzheimer

L. Ma et al. / Clinica Chimica Acta 444 (2015) 18–23

[88] [89]

[90]

[91] [92]

[93] [94]

[95]

[96] [97] [98]

[99]

[100]

disease, other dementias, and in age-matched controls. Arch Pathol Lab Med 2001; 125:510–2. Gonçalves NP, Vieira P, Saraiva M. Interleukin-1 signaling pathway as a therapeutic target in transthyretin amyloidosis. Amyloid 2014;21(3):175–84. François A, Terro F, Janet T, Rioux Bilan A, Paccalin M, Page G. Involvement of interleukin-1β in the autophagic process of microglia: relevance to Alzheimer's disease. J Neuroinflammation 2013;10:151. Millington C, Sonego S, Karunaweera N, et al. Chronic neuroinflammation in Alzheimer's disease: new perspectives on animal models and promising candidate drugs. Biomed Res Int 2014;309129. O'Banion MK. Does peripheral inflammation contribute to Alzheimer disease? Evidence from animal models. Neurology 2014;83(6):480–1. Lee S, Tong M, Hang S, et al. CSF and brain indices of insulin resistance, oxidative stress and neuro-inflammation in early versus late Alzheimer's disease. J Alzheimers Dis Parkinsonism 2013;31:128. Johnston H, Boutin H, Allan SM. Assessing the contribution of inflammation in models of Alzheimer's disease. Biochem Soc Trans 2011;39:886–90. Ghasemi R, Dargahi L, Haeri A, Moosavi M, Mohamed Z, Ahmadiani A. Brain insulin dysregulation: implication for neurological and neuropsychiatric disorders. Mol Neurobiol 2013;47:1045–65. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995;378: 785–9. Lee J, Kim MS. The role of GSK3 in glucose homeostasis and the development of insulin resistance. Diabetes Res Clin Pract 2007;77:S49–57. Lopez MF, Krastins B, Ning M. The role of apolipoprotein E in neurodegeneration and cardiovascular disease. Expert Rev Proteomics 2014;11(3):371–81. Londono C, DeKroon RM, Mocanu M, et al. Proteomic analysis of mice expressing human ApoE demonstrates no differences in global protein solubility between APOE 3 and APOE 4 young mice. Electrophoresis 2012;33(24):3745–55. McIntosh AM, Bennett C, Dickson D, et al. The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes). PLoS One 2012;10:e47760. Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 2013;9(2):106–18.

23

[101] Jagust WJ, Landau SM. Alzheimer's Disease Neuroimaging Initiative. Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging. J Neurosci 2012;32(50):18227–33. [102] Masoodi TA, Al Shammari SA, Al-Muammar MN, Alhamdan AA. Screening and evaluation of deleterious SNPs in APOE gene of Alzheimer's disease. Neurol Res Int 2012;480609. [103] Wang Z, Ma W, Rong Y, Liu L. The association between apolipoprotein E gene polymorphism and mild cognitive impairment among different ethnic minority groups in China. Int J Alzheimers Dis 2014;150628. [104] Gharesouran J, Rezazadeh M, Khorrami A, Ghojazadeh M, Talebi M. Genetic evidence for the involvement of variants at APOE, BIN1, CR1, and PICALM loci in risk of late-onset Alzheimer's disease and evaluation for interactions with APOE genotypes. J Mol Neurosci 2014 [Epub ahead of print]. [105] Coder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993;261: 921–3. [106] Kummer MP, Schwarzenberger R, Sayah-Jeanne S, et al. Pan-PPAR modulation effectively protects APP/PS1 mice from amyloid deposition and cognitive deficits. Mol Neurobiol 2014 [Epub ahead of print]. [107] Holscher C. Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. Biochem Soc Trans 2011;39:891–7. [108] Blázquez E, Velázquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and Alzheimer's disease. Front Endocrinol 2014;5:161. [109] Bloemer J, Bhattacharya S, Amin R, Suppiramaniam V. Impaired insulin signaling and mechanisms of memory loss. Prog Mol Biol Transl Sci 2014;121:413–49. [110] Ma L, Shao Z, Wang R, et al. The β-amyloid precursor protein analog P165 improves impaired insulin signal transduction in type 2 diabetic rats. Neurol Sci Nov 8 2014 [Epub ahead of print]. [111] de la Monte SM. Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art. Expert Opin Drug Deliv 2013;10:1699–709.