Impaired Brain Insulin Signaling Research Articles

A Review on Intranasal Insulin Drug Potential Effect on Alzheimer Disease in Type 2 Diabetic Patients

Massive evidence is available regarding the connection between Alzheimer disease and Diabetes Mellitus and their common pathological mechanisms, including impaired brain insulin signaling that can contribute to alteration of protein, glucose and lipid metabolism, chronic inflammation, oxidative stress, and mitochondrial dysfunction. However, the evidence is limited regarding the exploration of potential disease modifying therapies, which can prevent from progressive neuronal death, leading to cognitive impairment, which is the devastating end stage of Alzheimer. To enhance brain insulin, function a recent approach to mitigate Alzheimer symptoms is to centrally administer insulin is through intranasal delivery. To avoid the blood-brain barrier, a large amount of insulin can be administered intravenously (intranasally) by injecting it directly into the nasal cavity (BBB). In healthy adults, intranasal insulin has been shown to alter CNS measurements. Type 2 diabetics may benefit from an intranasal insulin medication that slows the progression of Alzheimer's disease, according to a new study. Keywords: Intranasal, insulin, Alzheimer, Diabetes.

A Bioinformatics Approach Toward Unravelling the Synaptic Molecular Crosstalk Between Alzheimer's Disease and Diabetes.

Background:Increasing evidence links impaired brain insulin signaling and insulin resistance to the development of Alzheimer’s disease (AD).Objective:This evidence prompted a search for molecular players common to AD and diabetes mellitus (DM).Methods:The work incorporated studies based on a primary care-based cohort (pcb-Cohort) and a bioinformatics analysis to identify central nodes, that are key players in AD and insulin signaling (IS) pathways. The interactome for each of these key proteins was retrieved and network maps were developed for AD and IS. Synaptic enrichment was performed to reveal synaptic common hubs.Results:Cohort analysis showed that individuals with DM exhibited a correlation with poor performance in the Mini-Mental State Examination (MMSE) cognitive test. Additionally, APOE ɛ2 allele carriers appear to potentially be relatively more protected against both DM and cognitive deficits. Ten clusters were identified in this network and 32 key synaptic proteins were common to AD and IS. Given the relevance of signaling pathways, another network was constructed focusing on protein kinases and protein phosphatases, and the top 6 kinase nodes (LRRK2, GSK3B, AKT1, EGFR, MAPK1, and FYN) were further analyzed.Conclusion:This allowed the elaboration of signaling cascades directly impacting AβPP and tau, whereby distinct signaling pathway play a major role and strengthen an AD-IS link at a molecular level.

Regulation of insulin transport across the blood‐brain barrier by CNS insulin receptor signaling

AbstractBackgroundImpairments in the regulation of central nervous system (CNS) insulin are clearly associated not only with metabolic syndrome and diabetes mellitus but also with Alzheimer’s disease (AD), age‐related cognitive decline, and mild cognitive impairment (MCI). Evidence exists for both decreased brain insulin levels and impaired brain insulin signaling (i.e., insulin resistance) as causes for this decreased insulin action. Insulin therapy can improve cognition in both healthy subjects as well as those suffering from cognitive impairments. While much of the focus in this area has been placed on overcoming CNS insulin resistance at the molecular level, we believe the impairment could lie at the blood‐brain barrier (BBB). CNS insulin is derived from the blood and crosses the BBB by a saturable transport system. Therefore, the insulin resistance observed in the CNS and at the neurovascular unit in these diseases could be a consequence of insulin deficiency and inadequate insulin BBB transport. Much focus has been placed on the peripheral mediators of insulin transport, with the direct role of the CNS often ignored. Therefore, the goal of this study was to investigate the communication of the neurovascular unit (NVU) in mediating CNS insulin levels in AD.MethodWe utilized the multiple‐time regression analysis technique to measure 125I‐insulin pharmacokinetics at the BBB. We were able to define the transport rate for 125I‐insulin and amount of vascular binding due to changes in CNS insulin receptor signaling. First, we inhibited CNS insulin receptor signaling by administering 1 μg S961 by intracerebroventricular (icv) injection. Second, we evaluated 125I‐insulin transport in mice lacking the insulin receptor in astrocytes.ResultAcute, broad inhibition of the CNS insulin receptor following icv delivery of S961, a selective antagonist, led to decreased 125I‐insulin transport across the BBB that was sex specific in CD‐1 mice. Follow‐up studies revealed the astrocytic insulin receptor may be responsible for this decreased transport as mice lacking the insulin receptor in astrocytes, GFAP insulin receptor knock‐out (GIRKO) mice, also have decreased 125I‐insulin BBB transport.ConclusionThese studies suggest the insulin receptor present on specific cell types within the CNS have a regulatory role in mediating insulin uptake by the brain.

Effect of Peripheral Insulin Administration on Phosphorylation of Tau in the Brain.

Abnormally hyperphosphorylated tau is the major protein of neurofibrillary tangles in Alzheimer's disease. Insulin activates PI3K-AKT signaling and regulates tau phosphorylation. Impaired brain insulin signaling is involved in Alzheimer's disease pathogenesis. However, the effect of peripheral insulin on tau phosphorylation is controversial. In the present study, we determined the effect of peripheral insulin administration on tau phosphorylation in brain. We intraperitoneally injected a super physiological dose of insulin to mice and analyzed PI3K-AKT signaling and tau phosphorylation in brains by western blots. We found that peripherally administered insulin activated the PI3K-AKT signaling pathway immediately in the liver, but not in the brain. Tau phosphorylation in the mouse brain was found to be first decreased (15 min) and then increased (30 min and 60 min) after peripheral insulin administration and these changes correlated inversely with body temperature and the level of brain protein O-GlcNAcylation. Maintaining body temperature of mice post peripheral insulin administration prevented the insulin/hypoglycemia-induced tau hyperphosphorylation after peripheral insulin administration. These findings suggest that peripheral insulin can induce tau hyperphosphorylation through both hypothermia and downregulation of brain protein O-GlcNAcylation during hypoglycemia.

Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance.

Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in-vivo molecular mechanisms of brain IR until recently has proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared to age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM+ exosomes in subjects with MDD as compared to age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM+ exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM+ exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM+ exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.

Pathophysiological Mechanisms Linking Type 2 Diabetes and Dementia: Review of Evidence from Clinical, Translational and Epidemiological Research.

Type 2 diabetes represents an increasing health burden world-wide and its prevalence in particularly higher in elderly population. Consistent epidemiological evidence suggests an increased risk of dementia associated to type 2 diabetes; the mechanisms underlying these associations, however, remain unclear. The study aims to review epidemiological, clinical and pre-clinical data that weigh on pathophysiological links, mechanisms of disease and associations between type 2 diabetes and dementia to identify areas of opportunity for future research. We searched the following electronic bibliographic databases: PUBMED, EMBASE, SCIELO, MEDLINE and OVID for clinical, translational and epidemiological research literature that summarize diabetes-related risk factors for dementia, metabolic and neurological changes associated to T2D, evidence of therapeutic approaches in type 2 diabetes and its pathophysiological implications for dementia. Type 2 diabetes mellitus increases risk for all-cause dementia, vascular dementia and Alzheimer's disease. The most evaluated mechanisms linking both disorders in pre-clinical studies include an increase in neuronal insulin resistance, impaired insulin signaling, pro-inflammatory state, mitochondrial dysfunction and vascular damage which increase deposition of β-amyloid, tau proteins and GSK3β, leading to an earlier onset of dementia in individuals with impairment in the glucose metabolism. Neuroimaging and neuropathology evidence linking cerebrovascular lesions, neurodegeneration and particularly small-vessel disease in the onset of dementia is consistent with the increased risk of incident dementia in type 2 diabetes, but consistent evidence of AD-related pathology is scarce. Epidemiological data shows increased risk of dementia related to hypoglycemic episodes, glycemic control, metabolic syndrome, insulin resistance and genetic predisposition, but the evidence is not consistent and statistical analysis might be affected by inconsistent covariate controlling. Therapeutic approaches for T2D have shown inconsistent result in relation to dementia prevention and delay of cognitive decline; lifestyle intervention, particularly physical activity, is a promising alternative to ameliorate the impact of disability and frailty on T2D-related dementia. Vascular disease, inflammation and impaired brain insulin signaling might occur in T2D and contribute to dementia risk. Evidence from epidemiological studies has not consistently reported associations that could integrate a unified mechanism of disease in humans. Evaluation of the effect of antidiabetic medications and non-pharmacological interventions in dementia prevention in type 2 diabetes is promising but has thus far offered inconsistent results.

Amyloid-beta impairs insulin signaling by accelerating autophagy-lysosomal degradation of LRP-1 and IR-β in blood-brain barrier endothelial cells in vitro and in 3XTg-AD mice

Aberrant insulin signaling constitutes an early change in Alzheimer's disease (AD). Insulin receptors (IR) and low-density lipoprotein receptor-related protein-1 (LRP-1) are expressed in brain capillary endothelial cells (BCEC) forming the blood-brain barrier (BBB). There, insulin may regulate the function of LRP-1 in Aβ clearance from the brain. Changes in IR-β and LRP-1 and insulin signaling at the BBB in AD are not well understood. Herein, we identified a reduction in cerebral and cerebrovascular IR-β levels in 9-month-old male and female 3XTg-AD (PS1M146V, APPSwe, and tauP301L) as compared to NTg mice, which is important in insulin mediated signaling responses. Reduced cerebral IR-β levels corresponded to impaired insulin signaling and LRP-1 levels in brain. Reduced cerebral and cerebrovascular IR-β and LRP-1 levels in 3XTg-AD mice correlated with elevated levels of autophagy marker LC3B. In both genotypes, high-fat diet (HFD) feeding decreased cerebral and hepatic LRP-1 expression and elevated cerebral Aβ burden without affecting cerebrovascular LRP-1 and IR-β levels. In vitro studies using primary porcine (p)BCEC revealed that Aβ peptides 1–40 or 1–42 (240 nM) reduced cellular levels and interaction of LRP-1 and IR-β thereby perturbing insulin-mediated signaling. Further mechanistic investigation revealed that Aβ treatment accelerated the autophagy-lysosomal degradation of IR-β and LRP-1 in pBCEC. LRP-1 silencing in pBCEC decreased IR-β levels through post-translational pathways further deteriorating insulin-mediated responses at the BBB. Our findings indicate that LRP-1 proves important for insulin signaling at the BBB. Cerebral Aβ burden in AD may accelerate LRP-1 and IR-β degradation in BCEC thereby contributing to impaired cerebral and cerebromicrovascular insulin effects.

1805-P: Insulin Regulates a Broad Network of Gene Expression in the Brain to Regulated Brain Metabolism and Neurotransmission

Impaired insulin signaling in brain leads to both metabolic and behavioral abnormalities. To understand the role of insulin on gene expression in the brain, we performed hyperinsulinemic-euglycemic clamps using physiological doses of insulin in C57BL/6 mice, and after 3 hours collected different brain regions and analyzed their transcriptomes by RNA Seq. In response to peripheral insulin, 1851 genes were up- or down-regulated in the hypothalamus by at least 50% (all P < 0.01). Other regions showed different responses with 205 genes significantly regulated by ≥ 50% in hippocampus and 131 regulated in nucleus accumbens. Insulin upregulated the pathway for very long chain fatty acyl-CoA synthesis in all three regions, but most insulin responsive genes were region specific. Thus, in hypothalamus, insulin modulated metabolism by suppressing the glycolysis and pentose phosphate pathway, while increasing expression of genes in the pyruvate dehydrogenase complex and cholesterol biosynthesis. Conversely, mice with streptozotocin diabetes displayed decreased expression of genes involved in the regulation of pyruvate dehydrogenase complex, very long-chain fatty acyl-CoA and cholesterol biosynthesis in hypothalamus, all of which were normalized by exogenous insulin. In addition, insulin regulated many genes in the hypothalamus involved in neurotransmission, including enhancing the expression of multiple GABA-A receptor subunits and suppressing many neuropeptides. Based on the transcriptional signature, changes in gene expression by insulin involve neurons, astrocytes, oligodendrocytes, microglia and endothelial cells. In summary, peripherally administered insulin rapidly and potently regulates expression of genes involved in neurotransmission, neuromodulation and brain metabolism, especially in the hypothalamus. This helps reroute substrate carbons to the biogenesis of plasma membrane for neuronal and glial function and synaptic remodeling. Disclosure W. Cai: None. T.M. Batista: None. R. Garcia Martin: None. A. Ramirez: None. M. Konishi: None. B.T. O'Neill: None. J.K. Kim: None. C. Kahn: Advisory Panel; Self; MedImmune. Board Member; Self; Kaleido Biosciences. Consultant; Self; AntriaBio, Inc., Cobalt Therapeutics, Flagship Pioneering. Research Support; Self; Alnylam.

Differential Expression of Apoptotic and Low-Grade Inflammatory Markers in Alzheimer Disease Compared to Diabetes Mellitus Type 1 and 2.

Neuroinflammation, impaired brain insulin signaling, and neuronal apoptosis may be interrelated in the pathophysiology of people with Alzheimer disease (AD) and diabetes, either type 1 or 2 diabetes (T1D or T2D, respectively). We studied 116 patients: 41 with AD, 20 with T1D, 21 with T2D, and 34 healthy controls. The number (n) of cytokine-secreting peripheral blood mononuclear cells (PBMCs) before and after mitogenic stimulation was determined for interleukin 1β (IL1β), interleukin 6 (IL6), tumor necrosis factor (TNF) by the enzyme-linked-immuno-spot assay. Serum concentrations of C-reactive protein (CRP) and Fas ligand (FASLG) were determined by ELISA. The studied subgroups did not differ in sex but differed in age. Higher CRP concentrations were detected in the AD group than in the T1D group (P = 0.02) and lower in controls (P < 0.001). The nPBMCs was higher in AD patients after stimulation than in basal conditions: after stimulation in nTNF (P < 0.001 vs T2D; P < 0.001 vs T1D; P = 0.001 vs control), nIL6 (P = 0.039 vs T2D; P < 0.001 vs T1D; P = 0.007 vs control), and nIL1β (P = 0.03 vs control). The nPBMCs increased after stimulation with ΡΜA in all the subgroups (P < 0.001). FASLG in the AD group displayed statistically higher concentrations than in all other subgroups (P < 0.001 vs T2D; P < 0.001 vs T1D; P = 0.012 vs control). The nPBMCs was positively correlated with plasma concentrations of FASLG in the AD subgroup. Patients with AD display a low-grade systemic inflammation compared to people with diabetes. The FAS-FASLG pathway has a potential role because FASLG concentrations are positively correlated with the inflammatory response in AD. However, this positive correlation cannot be seen in people with diabetes, at least not with the apoptotic markers used in the present study.

Formulation and optimization of intranasal nanolipid carriers of pioglitazone for the repurposing in Alzheimer’s disease using Box-Behnken design

Growing evidence suggest that Alzheimer’s disease (AD), the most common cause of dementia among the elderly is a metabolic disorder associated with impaired brain insulin signaling. Hence, the diabetic drug can be a therapeutic option for the management AD. The researches in this area are ongoing and Pioglitazone (PIO) is one of the most investigated diabetic drug in AD. Eventhough PIO treatment was found to improve AD significantly in the preclinical models, the poor blood-brain barrier (BBB) permeability and serious peripheral side effects limited its success in the clinical trials. The objective of the present study was to formulate and optimize intranasal (IN) nano lipid carriers (NLC) of PIO for its targeted delivery to the brain. A Box-Behnken design was employed to optimize the effect of three independent variables on two dependent variables. The optimized formulation had a particle size (PS) of 211.4 ± 3.54 nm and zeta potential of (ZP) of 14.9 ± 1.09 mv. The polydispersibility index (PDI) and entrapment efficiency (EE) was found to be 0.257 ± 0.108 and 70.18 ± 4.5% respectively. Storage stability studies performed has confirmed the stability of NLCs at 4 °C and 25 °C. The in-vitro drug release study has exhibited a sustained release of drug from the NLC. The formulation was observed to improve the nasal permeability of PIO ex-vivo significantly. Toxicity studies were performed to confirm the safety of formulation for the in-vivo administration. In-vivo biodistribution study in rats has shown a direct transport of drug from the nose to brain from the IN-NLC.

Neuroprotective Actions of Glucagon-Like Peptide-1 (GLP-1) Analogues in Alzheimer's and Parkinson's Diseases.

The current absence of effective treatments for Alzheimer's disease (AD) and Parkinson's disease (PD) reflects an incomplete knowledge of the underlying disease processes. Considerable efforts have been made to investigate the central pathological features of these diseases, giving rise to numerous attempts to develop compounds that interfere with such features. However, further characterization of the molecular targets within the interconnected AD and PD pathways is still required. Impaired brain insulin signaling has emerged as a feature that contributes to neuronal dysfunction in both AD and PD, leading to strategies aiming at restoring this pathway in the brain. Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for treatment of type 2 diabetes mellitus have been tested and have shown encouraging protective actions in experimental models of AD and PD as well as in initial clinical trials. We review studies revealing the neuroprotective actions of GLP-1 analogues in pre-clinical models of AD and PD and promising results from recent clinical trials.

Insulin Acutely Regulates Gene Expression in Brain–A New Potential Major Level of Control of Metabolism and Neurotransmission

While the brain is now recognized as an insulin sensitive tissue, and impaired insulin signaling in brain can lead to many metabolic and behavioral abnormalities, effects of insulin on gene expression in the brain remain largely unknown. To understand now this aspect of insulin action may impact physiology in vivo, we performed hyperinsulinemic-euglycemic clamps at low (4 mU/kg/min) and high (12 mU/kg/min) physiological doses of insulin in C57BL/6 mice, and after 3 hours collected different brain regions and analyzed their transcriptomes using RNA Seq. In response to low dose insulin infusion, 1851 genes were up- or down-regulated in the hypothalamus by at least 50% (all P &amp;lt; 0.01). This was more than 4-fold as the number of genes regulated in liver or muscle under the same conditions. Other regions showed different responses with 2significantly regulated by at least 50% in hippocampus and 131 regulated in nucleus accumbens. The most upregulated pathway in all three regions was that for very long chain fatty acyl-CoA synthesis, indicating an important role of insulin action on brain fatty acid metabolism. Most other insulin responsive genes in these three brain regions were distinct. In the hypothalamus, insulin played a key role in modulating genes involved in neurotransmission in the hypothalamus, including enhancing the GABA-A receptor signaling pathway and suppressing neuropeptide signaling pathways. Insulin also modulated metabolism in the hypothalamus by suppressing the glycolysis and pentose phosphate pathways, while increasing the pyruvate dehydrogenase complex and cholesterol biosynthesis. Thus, insulin action in the brain acutely and potently regulates expression of genes involved in brain metabolism, neurotransmission and neuromodulation. In this way, insulin re-routes the carbon source to the biogenesis of plasma membrane for neuronal and glial function and synaptic remodeling. Disclosure W. Cai: None. A. Ramirez: None. J. Dreyfuss: None. T.M. Batista: None. R. Garcia Martin: None. H. Pan: None. M.E. Li: None. B.T. O'Neill: None. J.K. Kim: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.

Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes

Diabetes and impaired brain insulin signaling are linked to the pathogenesis of Alzheimer's disease (AD). The association between diabetes and AD-associated amyloid pathology is stronger among carriers of the apolipoprotein E (APOE) ε4 gene allele, the strongest genetic risk factor for late-onset AD. Here we report that apoE4 impairs neuronal insulin signaling in human apoE-targeted replacement (TR) mice in an age-dependent manner. High-fat diet (HFD) accelerates these effects in apoE4-TR mice at middle age. In primary neurons, apoE4 interacts with insulin receptor and impairs its trafficking by trapping it in the endosomes, leading to impaired insulin signaling and insulin-stimulated mitochondrial respiration and glycolysis. In aging brains, the increased apoE4 aggregation and compromised endosomal function further exacerbate the inhibitory effects of apoE4 on insulin signaling and related functions. Together, our study provides novel mechanistic insights into the pathogenic mechanisms of apoE4 and insulin resistance in AD.

Brain GLP-1/IGF-1 Signaling and Autophagy Mediate Exendin-4 Protection Against Apoptosis in Type 2 Diabetic Rats.

Type 2 diabetes (T2D) is a modern socioeconomic burden, mostly due to its long-term complications affecting nearly all tissues. One of them is the brain, whose dysfunctional intracellular quality control mechanisms (namely autophagy) may upregulate apoptosis, leading to cognitive dysfunction and Alzheimer disease (AD). Since impaired brain insulin signaling may constitute the crosslink between T2D and AD, its restoration may be potentially therapeutic herein. Accordingly, the insulinotropic anti-T2D drugs from glucagon-like peptide-1 (GLP-1) mimetics, namely, exendin-4 (Ex-4), could be a promising therapy. In line with this, we hypothesized that peripherally administered Ex-4 rescues brain intracellular signaling pathways, promoting autophagy and ultimately protecting against chronic T2D-induced apoptosis. Thus, we aimed to explore the effects of chronic, continuous, subcutaneous (s.c.) exposure to Ex-4 in brain cortical GLP-1/insulin/insulin-like growth factor-1 (IGF-1) signaling, and in autophagic and cell death mechanisms in middle-aged (8months old), male T2D Goto-Kakizaki (GK) rats. We used brain cortical homogenates obtained from middle-aged (8months old) male Wistar (control) and T2D GK rats. Ex-4 was continuously administered for 28days, via s.c. implanted micro-osmotic pumps (5μg/kg/day; infusion rate 2.5μL/h). Peripheral characterization of the animal models was given by the standard biochemical analyses of blood or plasma, the intraperitoneal glucose tolerance test, and the heart rate. GLP-1, insulin, and IGF-1, their downstream signaling and autophagic markers were evaluated by specific ELISA kits and Western blotting. Caspase-like activities and other apoptotic markers were given by colorimetric methods and Western blotting. Chronic Ex-4 treatment attenuated peripheral features of T2D in GK rats, including hyperglycemia and insulin resistance. Furthermore, s.c. Ex-4 enhanced their brain cortical GLP-1 and IGF-1 levels, and subsequent signaling pathways. Specifically, Ex-4 stimulated protein kinase A (PKA) and phosphoinositide 3-kinase (PI3K)/Akt signaling, increasing cGMP and AMPK levels, and decreasing GSK3β and JNK activation in T2D rat brains. Moreover, Ex-4 regulated several markers for autophagy in GK rat brains (as mTOR, PI3K class III, LC3 II, Atg7, p62, LAMP-1, and Parkin), ultimately protecting against apoptosis (by decreasing several caspase-like activities and mitochondrial cytochrome c, and increasing Bcl2 levels upon T2D). Altogether, this study demonstrates that peripheral Ex-4 administration may constitute a promising therapy against the chronic complications of T2D affecting the brain.

Exercise Attenuates High-Fat Diet-induced Disease Progression in 3xTg-AD Mice.

Little is known regarding the therapeutic role of exercise against the risk of a high-fat diet (HFD) for Alzheimer's disease (AD) and AD-like cognitive deficits. This study aimed to investigate the therapeutic effect of treadmill running against HFD-induced progression in AD neuropathology and cognitive impairments in the triple-transgenic AD (3xTg-AD) mice. The 3xTg-AD mice were assigned to a chow diet (control, n = 10), an HFD (n = 10), or an HFD combined with exercise (HFD + EX, n = 10) group. Mice in the HFD were fed with a 60% fat diet for 20 wk. The HFD + EX mice were additionally subjected to treadmill running. Compared with the control mice, the HFD mice had impaired brain insulin signaling, exacerbated AD neuropathology, defects in synaptic stability/plasticity, and apoptotic neuronal cell death in conjunction with exacerbated cognitive deficits in the affected brain regions, which were all significantly alleviated in the HFD + EX mice. The current findings suggest that treadmill running protects against AD-like disease progression and cognitive deficits caused by an HFD in the 3xTg-AD mice.

Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory.

The role of insulin-regulated glucose transporter-4 (GluT4) in the brain is unclear. In the current study, we demonstrate that GluT4 is a critical component of hippocampal memory processes. Memory training increased hippocampal GluT4 translocation and memory acquisition was impaired by GluT4 blockade. Unexpectedly, whereas long-term inhibition of GluT4 impaired long-term memory, short-term memory was enhanced. These data further our understanding of the molecular mechanisms of memory and have particular significance for type 2 diabetes (in which GluT4 activity in the periphery is impaired) and Alzheimer's disease (which is linked to impaired brain insulin signaling and for which type 2 diabetes is a key risk factor). Both diseases cause marked impairment of hippocampal memory linked to hippocampal hypometabolism, suggesting the possibility that brain GluT4 dysregulation may be one cause of cognitive impairment in these disease states.

MTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease

A major obstacle to presymptomatic diagnosis and disease-modifying therapy for Alzheimer's disease (AD) is inadequate understanding of molecular mechanisms of AD pathogenesis. For example, impaired brain insulin signaling is an AD hallmark, but whether and how it might contribute to the synaptic dysfunction and neuron death that underlie memory and cognitive impairment has been mysterious. Neuron death in AD is often caused by cell cycle reentry (CCR) mediated by amyloid-β oligomers (AβOs) and tau, the precursors of plaques and tangles. We now report that CCR results from AβO-induced activation of the protein kinase complex, mTORC1, at the plasma membrane and mTORC1-dependent tau phosphorylation, and that CCR can be prevented by insulin-stimulated activation of lysosomal mTORC1. AβOs were also shown previously to reduce neuronal insulin signaling. Our data therefore indicate that the decreased insulin signaling provoked by AβOs unleashes their toxic potential to cause neuronal CCR, and by extension, neuron death.

Unaltered Prion Pathogenesis in a Mouse Model of High-Fat Diet-Induced Insulin Resistance

Epidemiological, clinical, and experimental animal studies suggest a strong correlation between insulin resistance and Alzheimer’s disease. In fact, type-2 diabetes is considered an important risk factor of developing Alzheimer’s disease. In addition, impaired insulin signaling in the Alzheimer’s disease brain may promote Aβ production, impair Aβ clearance and induce tau hyperphosphorylation, thereby leading to deterioration of the disease. The pathological prion protein, PrPSc, deposits in the form of extracellular aggregates and leads to dementia, raising the question as to whether prion pathogenesis may also be affected by insulin resistance. We therefore established high-fat diet-induced insulin resistance in tga20 mice, which overexpress the prion protein. We then inoculated the insulin-resistant mice with prions. We found that insulin resistance in tga20 mice did not affect prion disease progression, PrPSc deposition, astrogliosis or microglial activation, and had no effect on survival. Our study demonstrates that in a mouse model, insulin resistance does not significantly contribute to prion pathogenesis.

Targeting Insulin Signaling for the Treatment of Alzheimer's Disease.

Sporadic Alzheimer's disease (AD) is caused by multiple etiological factors, among which impaired brain insulin signaling and decreased brain glucose metabolism are important metabolic factors. Contrary to previous belief that insulin would not act in the brain, studies in the last three decades have proven important roles of insulin and insulin signaling in various biological functions in the brain. Impaired brain insulin signaling or brain insulin resistance and its role in the molecular pathogenesis of sporadic AD have been demonstrated. Thus, targeting brain insulin signaling for the treatment of cognitive impairment and AD has now attracted much attention in the field of AD drug discovery. This article reviews recent studies that target brain insulin signaling, especially those investigations on intranasal insulin administration and drugs that improve insulin sensitivity, including incretins, dipeptidyl peptidase IV inhibitors, thiazolidinediones, and metformin. These drugs have been previously approved for the treatment of diabetes mellitus, which could expedite their development for the treatment of AD. Although larger clinical trials are needed for validating their efficacy for the treatment of cognitive impairment and AD, results of animal studies and clinical trials available to date are encouraging.

Intracerebroventricular Streptozotocin Exacerbates Alzheimer-Like Changes of 3xTg-AD Mice

Alzheimer's disease (AD) involves several possible molecular mechanisms, including impaired brain insulin signaling and glucose metabolism. To investigate the role of metabolic insults in AD, we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month-old 3xTg-AD mice and studied the cognitive function as well as AD-like brain abnormalities, such as tau phosphorylation and Aβ accumulation, 3-6 weeks later. We found that STZ exacerbated impairment of short-term and spatial reference memory in 3xTg-AD mice. We also observed an increase in tau hyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling, and a decrease in synaptic plasticity and amyloid β peptides in the brain after STZ treatment. The expression of 20 AD-related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases, and apoptosis, was altered, suggesting that STZ disturbs multiple metabolic and cell signaling pathways in the brain. These findings provide experimental evidence of the role of metabolic insult in AD.