HHEX_23 AA Genotype Exacerbates Effect of Diabetes on Dementia and Alzheimer Disease: A Population-Based Longitudinal Study

BackgroundResearch has suggested that variations within the IDE/HHEX gene region may underlie the association of type 2 diabetes with Alzheimer disease (AD). We sought to explore whether IDE genes play a role in the association of diabetes with dementia, AD, and structural brain changes using data from two community-based cohorts of older adults and a subsample with structural MRI.ConclusionsA variant in the HHEX_23 gene interacts with diabetes to be associated with a substantially increased risk of dementia and AD, and with structural brain changes among dementia-free elderly people.     

Physiological effects of manipulating the level of insulin-degrading enzyme in insulin-producing cells of Drosophila

Insulin-degrading enzyme (IDE) degrades insulin and other peptides, including the Aβ peptide of Alzheimer's disease. However, the mechanism by which IDE acts on its substrates in vivo is unclear, and its role in pathogenesis of type 2 diabetes and Alzheimer's disease is controversial. Here, we show that in Drosophila knocking down IDE in insulin-producing cells (IPCs) of the brain results in increased body weight and fecundity, decreased circulating sugar levels, and reduced lifespan. Moreover, knocking down and over-expressing IDE in IPCs have opposite physiological effects. As mis-regulated insulin signaling in peripheral tissues is known to cause similar phenotypes, our data suggest a role for Drosophila IDE in determining the level of insulin-like peptides made by IPCs that systemically activate insulin signaling.     

The irreversible binding of amyloid peptide substrates to insulin-degrading enzyme

Insulin-degrading enzyme (IDE) is a conserved Zn2+metalloendopeptidase involved in insulin degradation and in the maintenance of brain steady-state levels of amyloid β peptide (Aβ) of Alzheimer’s disease (AD). Our recent demonstration that IDE and Aβ are capable of forming a stoichiometric and extremely stable complex raises several intriguing possibilities regarding the role of this unique protein-peptide interaction in physiological and pathological conditions. These include a protective cellular function of IDE as a “dead-end chaperone” alternative to its proteolytic activity and the potential impact of the irreversible binding of Aβ to IDE upon its role as a varicella zoster virus receptor. In a pathological context, the implications for insulin signaling and its relationship to AD pathogenesis are discussed. Moreover, our findings warrant further research regarding a possible general and novel interaction between amyloidogenic peptides and other Zn2+metallopeptidases with an IDE-like fold and a substrate conformation-dependent recognition mechanism.     

Insulin receptor mutation results in insulin resistance and hyperinsulinemia but does not exacerbate Alzheimer’s-like phenotypes in mice

Obesity is a risk factor for Alzheimer’s disease (AD), which is characterized by amyloid β depositions and cognitive dysfunction. Although insulin resistance is one of the phenotypes of obesity, its deleterious effects on AD progression remain to be fully elucidated. We previously reported that the suppression of insulin signaling in a mouse with a heterozygous mutation (P1195L) in the gene for the insulin receptor showed insulin resistance and hyperinsulinemia but did not develop diabetes mellitus [15]. Here, we generated a novel AD mouse model carrying the same insulin receptor mutation and showed that the combination of insulin resistance and hyperinsulinemia did not accelerate plaque formation or memory abnormalities in these mice. Interestingly, the insulin receptor mutation reduced oxidative damage in the brains of the AD mice. These findings suggest that insulin resistance is not always involved in the pathogenesis of AD.     

Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis

Type 2 diabetes mellitus (DM) appears to be a significant risk factor for Alzheimer disease (AD). Insulin and insulin-like growth factor-1 (IGF-1) also have intense effects in the central nervous system (CNS), regulating key processes such as neuronal survival and longevity, as well as learning and memory. Hyperglycaemia induces increased peripheral utilization of insulin, resulting in reduced insulin transport into the brain. Whereas the density of brain insulin receptor decreases during age, IGF-1 receptor increases, suggesting that specific insulin-mediated signals is involved in aging and possibly in cognitive decline. Molecular mechanisms that protect CNS neurons against β-amyloid-derived-diffusible ligands (ADDL), responsible for synaptic deterioration underlying AD memory failure, have been identified. The protection mechanism does not involve simple competition between ADDLs and insulin, but rather it is signalling dependent down-regulation of ADDL-binding sites. Defective insulin signalling make neurons energy deficient and vulnerable to oxidizing or other metabolic insults and impairs synaptic plasticity. In fact, destruction of mitochondria, by oxidation of a dynamic-like transporter protein, may cause synapse loss in AD. Moreover, interaction between Aβ and τ proteins could be cause of neuronal loss. Hyperinsulinaemia as well as complete lack of insulin result in increased τ phosphorylation, leading to an imbalance of insulin-regulated τ kinases and phosphatates. However, amyloid peptides accumulation is currently seen as a key step in the pathogenesis of AD. Inflammation interacts with processing and deposit of β-amyloid. Chronic hyperinsulinemia may exacerbate inflammatory responses and increase markers of oxidative stress. In addition, insulin appears to act as 'neuromodulator', influencing release and reuptake of neurotransmitters, and improving learning and memory. Thus, experimental and clinical evidence show that insulin action influences cerebral functions. In this paper, we reviewed several mechanisms by which insulin may affect pathophysiology in AD.     

Hyperinsulinemia is associated with increasing insulin secretion but not with decreasing insulin clearance in an age-related metabolic dysfunction mice model

Human life expectancy is increasing faster lately and, consequently, the number of patients with age-related diseases such as type 2 diabetes (T2D) is rising every year. Cases of hyperinsulinemia have been extensively reported in elderly subjects and this alteration in blood insulin concentration is postulated to be a cause of insulin resistance, which in some cases triggers T2D onset. Thus, it is important to know the underlying mechanisms of age-dependent hyperinsulinemia to find new strategies to prevent T2D in elderly subjects. Two processes control blood insulin concentration: Insulin secretion by the endocrine portion of the pancreas and insulin clearance, which occurs mainly in the liver by the action of the insulin-degrading enzyme (IDE). Here, we demonstrated that 10-month-old mice (old) display increased body and fat pad weight, compared with 3-month-old mice (control), and these alterations were accompanied by glucose and insulin intolerance. We also confirm hyperinsulinemia in the old mice, which was related to increased insulin secretion but not to reduced insulin clearance. Although no changes in insulin clearance were observed, IDE activity was lower in the liver of old compared with the control mice. However, this decreased IDE activity was compensated by increased expression of IDE protein in the liver, thus explaining the similar insulin clearance observed in both groups. In conclusion, at the beginning of aging, 10-month-old mice do not display any alterations in insulin clearance. Therefore, hyperinsulinemia is initiated primarily due to a higher insulin secretion in the age-related metabolic dysfunction in mice.     

AD认知功能障碍的代谢紊乱机制:脑胰岛素抵抗及其介导的PI3K/Akt信号通路受损

阿尔茨海默病(Alzheimer’s disease, AD)是一种以进行性痴呆为主要特征的中枢神经系统退行性疾病,其认知功能障碍可能与Ⅱ型糖尿病(type 2 diabetes, T2DM)诱发的胰岛素抵抗所损伤的PI3K/Akt胰岛素信号级联通路相关。胰岛素是调节机体新陈代谢的重要激素,通过与神经细胞表面的胰岛素受体结合激活PI3K/Akt信号通路,以调控葡萄糖、脂质的代谢。任何中间媒介功能紊乱所导致的脑胰岛素水平和胰岛素敏感性的降低都会损坏PI3K/Akt信号通路,诱发脑能量代谢障碍、Aβ沉积、Tau蛋白过度磷酸化,引起并加重AD认知功能障碍。因此,本文以PI3K/Akt胰岛素信号通路为主线,揭示了T2DM中脑胰岛素抵抗(insulin resistance, IR)与AD之间的复杂机制,旨在加深对脑IR介导的AD病理过程的系统性理解,借此为延缓或治疗AD的认知功能障碍提供理论基础。     

Diabetes as a risk factor for Alzheimer’s disease in the Middle East and its shared pathological mediators

The incidence of Alzheimer’s disease (AD) has risen exponentially worldwide over the past decade. A growing body of research indicates that AD is linked to diabetes mellitus (DM) and suggests that impaired insulin signaling acts as a crucial risk factor in determining the progression of this devastating disease. Many studies suggest people with diabetes, especially type 2 diabetes, are at higher risk of eventually developing Alzheimer's dementia or other dementias. Despite nationwide efforts to increase awareness, the prevalence of Diabetes Mellitus (DM) has risen significantly in the Middle East and North African (MENA) region which might be due to rapid urbanization, lifestyle changes, lack of physical activity and rise in obesity. Growing body of evidence indicates that DM and AD are linked because both conditions involve impaired glucose homeostasis and altered brain function. Current theories and hypothesis clearly implicate that defective insulin signaling in the brain contributes to synaptic dysfunction and cognitive deficits in AD. In the periphery, low-grade chronic inflammation leads to insulin resistance followed by tissue deterioration. Thus insulin resistance acts as a bridge between DM and AD. There is pressing need to understand on how DM increases the risk of AD as well as the underlying mechanisms, due to the projected increase in age related disorders. Here we aim to review the incidence of AD and DM in the Middle East and the possible link between insulin signaling and ApoE carrier status on Aβ aggregation, tau hyperphosphorylation, inflammation, oxidative stress and mitochondrial dysfunction in AD. We also critically reviewed mutation studies in Arab population which might influence DM induced AD. In addition, recent clinical trials and animal studies conducted to evaluate the efficiency of anti-diabetic drugs have been reviewed.     

The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid beta peptide: implications for Alzheimer disease pathogenesis

Insulin-degrading enzyme (IDE) is central to the turnover of insulin and degrades amyloid beta (Abeta) in the mammalian brain. Biochemical and genetic data support the notion that IDE may play a role in late onset Alzheimer disease (AD), and recent studies suggest an association between AD and diabetes mellitus type 2. Here we show that a natively folded recombinant IDE was capable of forming a stable complex with Abeta that resisted dissociation after treatment with strong denaturants. This interaction was also observed with rat brain IDE and detected in an SDS-soluble fraction from AD cortical tissue. Abeta sequence 17-27, known to be crucial in amyloid assembly, was sufficient to form a stable complex with IDE. Monomeric as opposed to aggregated Abeta was competent to associate irreversibly with IDE following a very slow kinetics (t(1/2) approximately 45 min). Partial denaturation of IDE as well as preincubation with a 10-fold molar excess of insulin prevented complex formation, suggesting that the irreversible interaction of Abeta takes place with at least part of the substrate binding site of the protease. Limited proteolysis showed that Abeta remained bound to a approximately 25-kDa N-terminal fragment of IDE in an SDS-resistant manner. Mass spectrometry after in gel digestion of the IDE .Abeta complex showed that peptides derived from the region that includes the catalytic site of IDE were recovered with Abeta. Taken together, these results are suggestive of an unprecedented mechanism of conformation-dependent substrate binding that may perturb Abeta clearance, insulin turnover, and promote AD pathogenesis.     

Neuroprotective role of Indirubin-3′-monoxime,a GSKβ inhibitor in high fat diet induced cognitive impairment in mice

Recent studies have highlighted that diabetes mellitus (DM) is a strong risk factor for Alzheimer’s disease (AD). Insulin resistance and/or hyperinsulinemia is one of the main characteristics of type 2 DM. Numerous epidemiological studies have demonstrated that insulin resistance contributes to AD pathogenesis. However the molecular mechanisms of association between these still remain elusive. Among the various possible mechanisms, the GSK-3β activity has been reported to be impaired in insulin-resistance, type 2 DM and AD. Thus, the present study was designed to explore the neuroprotective role of GSK3 β inhibitor, Indirubin-3′-monoxime (IMX) in insulin resistance induced cognitive impairment. Further, we have explored the possible molecular mechanism involved in cognitive impairment associated with insulin resistance. The mice subjected to high fat diet exhibited characteristic features of insulin resistance viz. increased serum glucose, triglycerides, cholesterol, insulin levels and impaired spatial learning and memory ability along with reduced brain insulin level, elevated oxidative stress and acetylcholinesterase (AChE) activity. The observed changes occurred concurrently with reduced brain derived neurotrophic factor. In contrast, the mice treated with IMX showed a significant reduction in plasma glucose, triglycerides, cholesterol, insulin levels and improvement in learning and memory performance, attenuated the oxidative stress and AChE activity. Moreover, IMX dose dependently augment the brain insulin and BDNF levels in HFD fed mice. Based upon these findings it could be suggested that GSK3 β inhibition could prove to be beneficial in insulin resistance induced cognitive deficit and this neuroprotection could be the result of enhanced BDNF based synaptic plasticity.     

Elevated risk of type 2 diabetes for development of Alzheimer disease: A key role for oxidative stress in brain

Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological data show that the incidence of AD increases with age and doubles every 5 years after 65 years of age. From a neuropathological point of view, amyloid-β-peptide (Aβ) leads to senile plaques, which, together with hyperphosphorylated tau-based neurofibrillary tangles and synapse loss, are the principal pathological hallmarks of AD. Aβ is associated with the formation of reactive oxygen (ROS) and nitrogen (RNS) species, and induces calcium-dependent excitotoxicity, impairment of cellular respiration, and alteration of synaptic functions associated with learning and memory. Oxidative stress was found to be associated with type 2 diabetes mellitus (T2DM), which (i) represents another prevalent disease associated with obesity and often aging, and (ii) is considered to be a risk factor for AD development. T2DM is characterized by high blood glucose levels resulting from increased hepatic glucose production, impaired insulin production and peripheral insulin resistance, which close resemble to the brain insulin resistance observed in AD patients. Furthermore, growing evidence suggests that oxidative stress plays a pivotal role in the development of insulin resistance and vice versa. This review article provides molecular aspects and the pharmacological approaches from both preclinical and clinical data interpreted from the point of view of oxidative stress with the aim of highlighting progresses in this field.     

大脑胰岛素信号途径受损导致2型糖尿病时阿尔茨海默病发病风险增高

大脑胰岛素不仅可调节血糖,而且可改善记忆和认知,而大脑胰岛素缺乏常导致Alzheimer病（Alzheimer’s disease, AD）的发生. 本研究检测了正常及2型糖尿病（type 2 diabetes, T2D）大鼠外周及大脑胰岛素信号传导途径,以探讨T2D时由于大脑胰岛素异常导致AD发病的可能性.以同龄正常SD大鼠为对照（CTL组）,高糖、高脂、高蛋白饮食加链脲佐菌素（streptozotocin, STZ）腹腔注射建造T2D大鼠模型（T2D组）.葡萄糖氧化酶法检测血浆血糖,放免法检测脑脊液及血浆胰岛素,免疫印迹技术检测大脑海马tau蛋白上部分位点磷酸化水平,大脑及肝脏、肌肉组织胰岛素信号传导途径中磷脂酰肌醇3 激酶（phosphatidylinositol 3 kinase, PI3K）/ 蛋白激酶B（protein kinase B,Akt)、糖原合成激酶3β（glycogen synthase kinase 3β, GSK 3β）活性. 结果显示：和对照组相比,T2D大鼠血浆葡萄糖水平及胰岛素水平显著升高,脑脊液胰岛素水平显著降低,大脑海马组织tau蛋白上所检测位点均呈过度磷酸化改变,海马及外周组织（肝脏、肌肉）胰岛素信号传导途径PI3K/Akt活性均显著下降,GSK 3β活性升高. 研究结果表明：2型糖尿病大鼠大脑胰岛素缺乏及其信号传导途径下调可能是导致阿尔茨海默病发病的重要原因.     

Intrahippocampal administration of a domain antibody that binds aggregated amyloid-β reverses cognitive deficits produced by diet-induced obesity

BackgroundThe prevalence of high fat diets (HFD), diet-induced obesity (DIO) and Type 2 diabetes continues to increase, associated with cognitive impairment in both humans and rodent models. Mechanisms transducing these impairments remain largely unknown: one possibility is that a common mechanism may be involved in the cognitive impairment seen in obese and/or diabetic states and in dementia, specifically Alzheimer's disease (AD). DIO is well established as a risk factor for development of AD. Oligomeric amyloid-β (Aβ) is neurotoxic, and we showed that intrahippocampal oligomeric Aβ produces cognitive and metabolic dysfunction similar to that seen in DIO or diabetes. Moreover, animal models of DIO show elevated brain Aβ, a hallmark of AD, suggesting that this may be one source of cognitive impairment in both conditions.MethodsIntrahippocampal administration of a novel anti-Aβ domain antibody for aggregated Aβ, or a control domain antibody, to control or HFD-induced DIO rats. Spatial learning measured in a conditioned contextual fear (CCF) task after domain antibody treatment; postmortem, hippocampal NMDAR and AMPAR were measured.ResultsDIO caused impairment in CCF, and this impairment was eliminated by intrahippocampal administration of the active domain antibody. Measurement of hippocampal proteins suggests that DIO causes dysregulation of hippocampal AMPA receptors, which is also reversed by acute domain antibody administration.ConclusionsOur findings support the concept that oligomeric Aβ within the hippocampus of DIO animals may not only be a risk factor for development of AD but may also cause cognitive impairment before the development of dementia.General Significance and InterestOur work integrates the engineering of domain antibodies with conformational- and sequence-specificity for oligomeric amyloid beta with a clinically relevant model of diet-induced obesity in order to demonstrate not only the pervasive effects of obesity on several aspects of brain biochemistry and behavior, but also the bioengineering of a successful treatment against the long-term detrimental effects of a pre-diabetic state on the brain. We show for the first time that cognitive impairment linked to obesity and/or insulin resistance may be due to early accumulation of oligomeric beta-amyloid in the brain, and hence may represent a pre-Alzheimer's state.     

Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions

Alzheimer disease (AD) is sometimes referred to as type III diabetes because of the shared risk factors for the two disorders. Insulin resistance, one of the major components of type II diabetes mellitus (T2DM), is a known risk factor for AD. Insulin resistance increases amyloid-β peptide (Aβ) generation, but the exact mechanism underlying the linkage of insulin resistance to increased Aβ generation in the brain is unknown. In this study, we investigated the effect of insulin resistance on amyloid β (A4) precursor protein (APP) processing in mice fed a high-fat diet (HFD), and diabetic db/db mice. We found that insulin resistance promotes Aβ generation in the brain via altered insulin signal transduction, increased BACE1/β-secretase and γ-secretase activities, and accumulation of autophagosomes. Using an in vitro model of insulin resistance, we found that defects in insulin signal transduction affect autophagic flux by inhibiting the mechanistic target of rapamycin (MTOR) pathway. The insulin resistance-induced autophagosome accumulation resulted in alteration of APP processing through enrichment of secretase proteins in autophagosomes. We speculate that the insulin resistance that underlies the pathogenesis of T2DM might alter APP processing through autophagy activation, which might be involved in the pathogenesis of AD. Therefore, we propose that insulin resistance-induced autophagosome accumulation becomes a potential linker between AD and T2DM.     

Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease

The quality control of protein homoeostasis deteriorates with aging, causing the accumulation of misfolded proteins and neurodegeneration. Thus, in AD (Alzheimer's disease), soluble oligomers, protofibrils and fibrils of the Aβ (amyloid β-peptide) and tau protein accumulate in specific brain regions. This is associated with the progressive destruction of synaptic circuits controlling memory and higher mental function. The primary signalling mechanisms that (i) become defective in AD to alter the normal proteostasis of Aβ and tau, and (ii) initiate a pathophysiological response to cause cognitive decline, are unclear. The IIS [insulin/IGF-1 (insulin-like growth factor 1)-like signalling] pathway is mechanistically linked to longevity, protein homoeostasis, learning and memory, and is emerging to be central to both (i) and (ii). This pathway is aberrantly overactivated in AD brain at the level of increased activation of the serine/threonine kinase Akt and the phosphorylation of its downstream targets, including mTOR (mammalian target of rapamycin). Feedback inhibition of normal insulin/IGF activation of the pathway also occurs in AD due to inactivation of IRS-1 (insulin receptor substrate 1) and decreased IRS-1/2 levels. Pathogenic forms of Aβ may induce aberrant sustained activation of the PI3K (phosphoinositide 3-kinase)/Akt signal in AD, also causing non-responsive insulin and IGF-1 receptor, and altered tau phosphorylation, conformation and function. Reducing IIS activity in animal models by decreasing IGF-1R levels or inhibiting mTOR activity alters Aβ and tau protein homoeostasis towards less toxic protein conformations, improves cognitive function and extends healthy lifespan. Thus normalizing IIS dysfunction may be therapeutically relevant in abrogating Aβ and tau proteotoxicity, synaptic dysfunction and cognitive decline in AD.     

Distinct inflammatory phenotypes of microglia and monocyte‐derived macrophages in Alzheimer's disease models: effects of aging and amyloid pathology

Alzheimer's disease (AD) is a neurodegenerative disease characterized by formation of amyloid‐β (Aβ) plaques, activated microglia, and neuronal cell death leading to progressive dementia. Recent data indicate that microglia and monocyte‐derived macrophages (MDM) are key players in the initiation and progression of AD, yet their respective roles remain to be clarified. As AD occurs mostly in the elderly and aging impairs myeloid functions, we addressed the inflammatory profile of microglia and MDM during aging in TgAPP/PS1 and TgAPP/PS1dE9, two transgenic AD mouse models, compared to WT littermates. We only found MDM infiltration in very aged mice. We determined that MDM highly expressed activation markers at basal state. In contrast, microglia exhibited an activated phenotype only with normal aging and Aβ pathology. Our study showed that CD14 and CD36, two receptors involved in phagocytosis, were upregulated during Aβ pathogenesis. Moreover, we observed, at the protein levels in AD models, higher production of pro‐inflammatory mediators: IL‐1β, p40, iNOS, CCL‐3, CCL‐4, and CXCL‐1. Taken together, our data indicate that microglia and MDM display distinct phenotypes in AD models and highlight the specific effects of normal aging vs Aβ peptides on inflammatory processes that occur during the disease progression. These precise phenotypes of different subpopulations of myeloid cells in normal and pathologic conditions may allow the design of pertinent therapeutic strategy for AD.     

Leptin inhibits amyloid β-protein degradation through decrease of neprilysin expression in primary cultured astrocytes

Pathogenesis of Alzheimer’s disease (AD) is characterized by accumulation of extracellular deposits of amyloid β-protein (Aβ) in the brain. The steady state level of Aβ in the brain is determined by the balance between its production and removal; the latter occurring through egress across blood and CSF barriers as well as Aβ degradation. The major Aβ-degrading enzymes in the brain are neprilysin (NEP) and insulin-degrading enzyme (IDE), which may promote Aβ deposition in patients with sporadic late-onset AD. Epidemiological studies have suggested an inverse relationship between the adipocytokine leptin levels and the onset of AD. However, the mechanisms underlying the relationship remain uncertain. We investigated whether leptin is associated with Aβ degradation by inducing NEP and IDE expression within primary cultured astrocytes. Leptin significantly decreased the expression of NEP but not IDE in a concentration- and time-dependent manner through the activation of extracellular signal-regulated kinase (ERK) in cultured rat astrocytes. Furthermore, leptin inhibited the degradation of exogenous Aβ in primary cultured astrocytes. These results suggest that leptin suppresses Aβ degradation by NEP through activation of ERK.