Avoid toxins that inflame the brain causing Alzheimer

. 2012 Jan; 9(1): 35–66.
Published online 2012 Jan. doi: 10.2174/156720512799015037
PMCID: PMC3349985
PMID: 22329651

Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer’s Disease

Abstract

Alzheimer’s disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.

Keywords: Alzheimer’s disease, dementia, neurofibrillary tangles, neurodegeneration cascade.

ALZHEIMER’S DISEASE AND BRAIN GLUCOSE METABOLISM

Alzheimer’s disease [AD] is the most common cause of dementia in North America, and over the past several decades, the prevalence rates of sporadic AD have become epidemic []. Although the clinical diagnosis of AD is based on criteria set by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS/ ADRDA) and DSM-IV criteria [], embracement of additional tools such as neuroimaging and standardized biomarker panels could facilitate early detection of disease []. Characteristic neuropathological hallmarks of AD include: neuronal loss, abundant accumulations of abnormal, hyperphosphorylated cytoskeletal proteins in neuronal perikarya and dystrophic fibers, and increased expression and abnormal processing of amyloid-beta precursor protein (AβPP), leading to AβPP-Aβ peptide deposition in neurons, plaques, and vessels. For nearly three decades, the dominant trends have been to interpret selected AD-associated abnormalities, namely the hyper-phosphorylation of tau and deposition of AβPP-Aβ as causal rather than consequential to the neurodegeneration cascade. This approach posed significant limitations on the scope of investigation and the goals with respect to designing new treatments; ergo, success has been either modest or disappointing. On the other hand, due to collected contributions of a number of researchers, the field has recently become more receptive to alternative concepts, opening the doors to exciting new avenues of investigation and therapeutic strategies.

Growing evidence supports the concept that AD fundamentally represents a metabolic disease in which brain glucose utilization and energy production are impaired []. Metabolic abnormalities have been linked to brain insulin and insulin-like growth factor (IGF) resistance with disruption of signaling pathways that regulate neuronal survival, energy production, gene expression, and plasticity []. On a cellular basis, inhibition of insulin/IGF signaling contributes to AD-type neurodegeneration by increasing: 1) the activity of kinases that aberrantly phosphorylate tau; 2) expression of AβPP and accumulation of AβPP-Aβ; 3) levels of oxidative and endoplasmic reticulum (ER) stress; 4) the generation of reactive oxygen and reactive nitrogen species that damage proteins, RNA, DNA, and lipids; 5) mitochondrial dysfunction; and 6) activation of pro-inflammatory and pro-death cascades. On a functional basis, insulin/IGF resistance causes down-regulation of target genes that are needed for cholinergic homeostasis, and it compromises systems that mediate neuronal plasticity, memory, and cognition.

The gold standard for definitively diagnosing AD is to perform a postmortem examination of the brain, with the objective of demonstrating beyond-normal aging associated densities of neurofibrillary tangles, neuritic plaques, and AβPP-Aβ deposits in corticolimbic structures, bearing in mind that neurodegeneration frequently involves multiple other cortical regions as well. The common thread among these characteristic lesions is that they harbor insoluble aggregates of abnormally phosphorylated and ubiquitinated tau, and neurotoxic AβPP-Aβ in the form of oligomers, fibrillar aggregates, or extracellular plaques. Secreted AβPP-Aβ oligomers have been demonstrated to be neurotoxic and to inhibit hippocampal long-term potentiation, i.e. synaptic plasticity [].

Ultimately, to improve our capacity for diagnosis and treatment, we should be able to connect the development and progression of neuropathological lesions with the molecular, biochemical, physiological, neuro-imaging, and clinical abnormalities that correlate with AD. Therefore, gaining a better understanding of the pathophysiology of these lesions could improve our current diagnostic and treatment approaches to AD. One way to begin the process in earnest is to acknowledge that the rigid employment of standardized criteria for diagnosing AD, in fact, restricts our ability to fully comprehend the underlying disease process. For example, in addition to the characteristic lesions noted above, AD is associated with loss of neurons, fibers, and synapses, disruption of the cortical-laminar architecture, gliosis, proliferation of dystrophic neurites, and neuro-inflammatory responses, including microglial cell activation. For unclear reasons, these abnormalities are not systematically quantified, and consequently, they are not routinely incorporated into the AD diagnostic equation. At the same time, many basic cellular, molecular, biochemical, and structural abnormalities in AD overlap with those in other neurodegenerative diseases such as dementia with Lewy bodies, fronto-temporal dementias, and multiple systems atrophy, indicating that one or two biomarkers might not be sufficient to consistently and accurately diagnose AD.

Hints that AD could represent a metabolic disease emerged from studies showing that the early stages of AD were marked by deficits cerebral glucose utilization [], and that as the disease progressed, metabolic and physiological abnormalities worsened [,]. Subsequently, AD was shown to be associated with brain insulin resistance and insulin deficiency, with significant abnormalities in the expression of genes and activation of kinases that are regulated by insulin and insulin-like growth factor (IGF) signaling []. Moreover, it was shown that in AD, progressive declines in cerebral glucose utilization, and deficits in insulin signaling and insulin-responsive gene expression worsen with severity of disease. In particular, insulin/IGF regulated genes, including choline acetyltransferase, tau, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which mediate cholinergic/cognitive, neuronal cytoskeletal, and metabolic functions, are suppressed in AD []. Insulin resistance mediated impairments in energy metabolism lead to oxidative stress, generation of reactive oxygen species (ROS), DNA damage, and mitochondrial dysfunction, all of which drive pro-apoptosis, pro-inflammatory, and pro-AβPP-Aβ cascades. Experimental animals in which brain insulin receptor expression and function were suppressed exhibited cognitive impairment and neurodegeneration with features that overlap with AD [].

In AD brains, deficits in insulin/IGF signaling are due to the combined effects of insulin/IGF resistance and deficiency. Insulin/IGF resistance is manifested by reduced levels of insulin/IGF receptor binding and decreased responsiveness to insulin/IGF stimulation, while the trophic factor deficiency is associated with reduced levels of insulin polypeptide and gene expression in brain and cerebrospinal fluid [,]. In essence, AD can be regarded as a form of brain diabetes that has elements of both insulin resistance and insulin deficiency. To consolidate this concept, we proposed that AD be referred to as, “Type 3 diabetes” [,].

INSULIN AND INSULIN-LIKE GROWTH FACTOR ACTIONS IN THE BRAIN

In the central nervous system (CNS), insulin and IGF signaling play critical roles in regulating and maintaining cognitive function. Insulin, IGF-1 and IGF-2 polypeptide and receptor genes are expressed in neurons [] and glial cells [] throughout the brain, and their highest levels of expression are in structures typically targeted by neurodegenerative diseases [,]. Insulin and IGFs regulate a broad range of neuronal functions throughout life, from embryonic and fetal development to adulthood. The corresponding signaling pathways are activated by insulin and IGF binding to their own receptors, resulting in phosphorylation and activation of intrinsic receptor tyrosine kinases. Subsequent interactions between the phosphorylated receptors and insulin receptor substrate (IRS) molecules promote transmission of downstream signals that inhibit apoptosis, and stimulate growth, survival, metabolism, and plasticity. Anti-apoptotic mechanisms inhibited by insulin/IGF stimulation include BAD (inhibitor of Bcl-2), Forkhead Box O (FoxO), glycogen synthase kinase 3β (GSK-3β), and nuclear factor kappa B (NF-κB). GSK-3β regulates Wnt signaling by phosphorylating β-catenin and thereby targeting it for ubiquitin/proteosome-mediated degradation. Wnt signaling mediates synaptic plasticity in the CNS. Therefore, major functions supported by the insulin/IGF signaling axis include, neuronal growth, survival, differentiation, migration, energy metabolism, gene expression, protein synthesis, cytoskeletal assembly, synapse formation, neurotransmitter function, and plasticity [,]. Correspondingly, impaired signaling through insulin and IGF receptors has dire consequences with respect to the structural and functional integrity of the CNS.

IMPAIRED INSULIN/IGF SIGNALING AND TAU PATHOLOGY IN AD

The major neuronal cytoskeletal lesions that correlate with severity of dementia in AD, including neurofibrillary tangles and dystrophic neurites, contain aggregated and ubiquitinated insoluble fibrillar tau. In other words, tau accumulation and pathology are the most significant structural correlates of dementia in AD [,]. In AD, tau, a microtubule-associated protein, gets hyperphosphorylated due to inappropriate activation of several proline-directed kinases, including GSK-3β. As a result, tau protein misfolds and self-aggregates into insoluble fibrillar structures [paired helical filaments and straight filaments] that form neurofibrillary tangles, dystrophic neurites, and neuropil threads []. Intra-neuronal accumulations of fibrillar tau disrupt neuronal cytoskeletal networks and axonal transport, leading to synaptic disconnection and progressive neurodegeneration []. Besides fibrillar tau, pre-fibrillar tau can aggregate, forming soluble tau oligomers or insoluble granular tau, which contribute to neurodegeneration by causing synaptic disconnection and neuronal death []. The eventual ubiquitination of hyper-phosphorylated tau [], combined with dysfunction of the ubiquitin-proteasome system [], cause further accumulation of insoluble fibrillar tau, oxidative stress, and ROS generation, which together promote neuronal apoptosis, mitochondrial dysfunction, and necrosis in AD [].

Growing evidence suggests that many of the aforementioned cellular aspects of AD neurodegeneration may be caused by brain insulin/IGF resistance [,] which, as in other brain insulin-resistance states, results in inhibition of downstream pro-growth and pro-survival signaling pathways (Fig. 11) []. Tau gene expression and phosphorylation are regulated by insulin and IGF stimulation [,]. In AD, brain insulin and IGF resistance result in decreased signaling through phosphoinositol-3-kinase (PI3K), Akt [,], and Wnt/β-catenin [], and increased activation of glycogen synthase kinase 3β (GSK-3β) []. GSK-3β over-activation is partly responsible for the hyper-phosphorylation of tau, which leads to tau misfolding and fibril aggregation []. In addition, tau hyper-phosphorylation in AD is mediated by increased activation of cyclin-dependent kinase 5 (cdk-5) and c-Abl kinases [,], and inhibition of protein phosphatases 1 and 2A [,,]. Besides hyper-phosphorylation, tau pathology in AD is mediated by impaired tau gene expression due to reduced insulin and IGF signaling []. Consequences include, failure to generate sufficient quantities of normal soluble tau protein, vis-a-vis accumulation of hyper-phosphorylated insoluble fibillar tau, and attendant exacerbation of cytoskeletal collapse, neurite retraction, and synaptic disconnection.

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Roles of brain insulin deficiency and brain insulin resistance in Tau pathology. Tau protein is normally regulated by insulin and IGF signalling. Insulin deficiency [effective trophic factor withdrawal] and insulin resistance lead to the over-activation of kinases and inhibition of phosphatases, which result in hyper-phosphorylation of tau. Attendant increased oxidative stress leads to ROS generation and ubiquitination, followed by misfolding of Tau. Misfolded tau aggregates and forms insoluble twisted fibrils that are neurotoxic and mediate dementia-associated neuropathological processes, i.e. neurofibrillary tangle formation, proliferation of dystrophic neuritis and neuropil threads, and synaptic disconnection.

INSULIN/IGF RESISTANCE AND AMYLOID-BETA (AΒ) NEUROTOXICITY

AD is associated with dysregulated expression and processing of amyloid precursor protein (AβPP), resulting in the accumulation of AβPP-Aβ (Aβ) oligomeric fibrils or insoluble larger aggregated fibrils (plaques) that are neurotoxic (Fig. 22). Pathophysiologically, increased AβPP gene expression, together with altered proteolysis, result in accumulation of 40 or 42 amino acid length Aβ peptides that can aggregate. In familial forms of AD, mutations in the AβPP, presenilin 1 (PS1), and PS2 genes, or inheritance of the Apoliprotein E ε4 (ApoE- ε4) allele, are responsible for increased synthesis and deposition of Aβ peptides in the brain. However, in sporadic AD, which accounts for 90% or more of the cases, the causes of Aβ accumulation and toxicity are still under intense investigation. Over the past few years, interest in the role of impaired insulin/IGF signaling as either the cause or consequence of dysregulated AβPP-Aβ expression and protein processing has grown.

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Brain insulin resistance and AβPP-Aβ deposition and toxicity. Brain insulin resistance caused by peripheral insulin resistance diseases or primary toxic and neurodegenerative processes in the brain promote neuroinflammation and increased expression of AβPP. Throught the action of Beta and Gamma secretases, AbPP is cleaved to generate excessive 40-42 kD AβPP-Aβ peptides that aggregate and form insoluble fibrils and plaques, or oligomers and AβPP-Aβ-derived diffusible ligands (ADDLs), which are neurotoxic. AβPP-Aβ oligomers and ADDLs promote oxidative stress and increased activation of kinases that lead to Tau hyperphosphorylation, and its eventual ubiquitination, misfolding, and aggregation. AβPP-Aβ oligomers and ADDLs may also block insulin receptor function and contribute to insulin resistance. Carriers of the ApoE e4 allele or Presenilin mutations are predisposed to excessive and abnormal AβPP cleavage, and AβPP-Aβ accumulation, aggregation, and fibril formation, correlating with increased rates and familial occurrences of AD.

The concept that Aβ toxicity causes insulin resistance, and the opposing argument that brain insulin resistance with attendant oxidative stress and neuro-inflammation promotes Aβ accumulation and toxicity are both supported by experimental data. For example, studies have established that insulin stimulation accelerates trafficking of Aβ from the trans-Golgi network, where it is generated, to the plasma membrane, and that insulin stimulates Aβ extracellular secretion [] and inhibits its intracellular accumulation and degradation by insulin-degrading enzyme [,]. Although it remains uncertain as to whether these physiological actions of insulin on AβPP processing contribute to Aβ burden, what is apparent is that impaired insulin signaling can disrupt both the processing of AβPP and clearance of Aβ []. The accumulation of Aβ exacerbates the problem because Aβ disrupts insulin signaling by competing with insulin, or reducing the affinity of insulin binding to its own receptor [,]. In addition, AβPP oligomers inhibit neuronal transmission of insulin-stimulated signals by desensitizing and reducing the surface expression of insulin receptors. Furthermore, intracellular AβPP-Aβ directly interferes with PI3 kinase activation of Akt, which leads to impaired survival signaling, increased activation of GSK-3β, and hyper-phosphorylation of tau. Hyper-phosphorylated tau is prone to misfold, aggregate, and become ubiquitinated, leading to the formation of dementia-associated paired-helical filament-containing neuronal cytoskeletal lesions. Since IGF-1 or IGF-2 suppression of GSK-3β activity [] reduces the neurotoxic effects of AβPP [], the neuro-protective properties of these and related trophic factors could be exploited for therapeutic purposes in AD.

INSULIN/IGF RESISTANCE, OXIDATIVE STRESS, AND METABOLIC DYSFUNCTION IN AD

Insulin and IGF signaling pathways regulate glucose utilization, metabolism, and ATP synthesis needed for cellular homeostasis and dynamic modulation of a broad range of functions (Tables 1,1,22). Deficits in cerebral glucose utilization and energy metabolism occur very early in the course of AD, such that they are detectable either prior to, or coincident with the initial stages of cognitive dysfunction [,,]. These findings lend strong support the concept that impairments in insulin signaling have important roles in the pathogenesis of AD []. Glucose uptake and utilization in brain are dependent upon glucose transport. Glucose transporter 4 (GLUT4) is abundantly expressed along with insulin receptors, in medial temporal lobe structures, which notably are major targets of AD neurodegeneration. Insulin stimulates GLUT4 gene expression and protein trafficking from the cytosol to the plasma membrane to modulate glucose uptake and utilization. Therefore, insulin stimulation of GLUT4 is critical to the regulation of neuronal metabolism and the generation of energy needed for memory and cognition. Although postmortem brain studies have not detected significant reductions in GLUT4 expression in AD [], the well-documented deficits in brain glucose utilization and energy metabolism vis-a-vis brain insulin/IGF resistance could instead be mediated by impairments in GLUT4 trafficking between the cytosol and plasma membrane.

Table 1.

Metabolic Hypothesis of Alzheimer’s Disease-Consequences of Brain Insulin Resistance

Impairment Adverse Effect Role in Alzheimer’s Disease
GLUT4 function Reduced glucose uptake and utilization Energy deficits; compromised homeostatic functions, disruption of neuronal cytoskeleton, synaptic disconnection
Insulin receptor function Decreased signaling through IRS, PI3K-Akt Reduced neuronal and oligodendroglial survival, neuronal plasticity, myelin maintenance
Increased activation of GSK-3β and phosphatases that negatively regulate insulin signaling Increased tau phosphorylation, oxidative stress, neuro-inflammation, pro-apoptosis signaling
Decreased Wnt signaling
Reduced insulin-responsive gene expression Reduced choline acetyltransferase expression –> deficits in acetylcholine
Decreased GAPDH expression, further impairment of glucose metabolism
Insulin receptor function or hyper-insulinemia Endothelial cell injury, intimal thickening, and vessel wall fibrosis Microvascular disease and cerebral hypoperfusion
Mitochondrial function Increased oxidative stress, ROS, RNS DNA damage, lipid peroxidation, energy deficits, cell death, increased AβPP expression, Aβ42 deposition and fibrillarization
Myelin maintenance Myelin breakdown, increased generation of ceramides and other toxic sphingolipids; lipid peroxidation; ROS Increased neuro-inflammation, oxidative stress, pro-apoptosis signaling, further insulin resistance
White matter atrophy due to fiber and myelin loss
Insulin/IGF availability Trophic factor withdrawal Death or impaired function of insulin/IGF dependent neurons and glial cells
Hyperglycemia Accumulation of advanced glycation end-products Disrupts removal of Aβ42

Abbreviations: GLUT4=glucose transporter 4; IRS= insulin receptor substrate; PI3K= phosphoinositol-3- kinase; GSK-3β = glycogen synthase kinase 3β; GAPDH=glyceraldehyde-3-phosphate dehydrogenase; ROS=reactive oxygen species; RNS=reactive nitrogen species; AβPP= amyloid-β – precursor protein; Aβ 42=amyloid beta peptide-42 amino acids 1-42 cleavage product; IGF=insulin-like growth factor.

Table 2.

Neuropathologic Processes Contributing to Brain Insulin Resistance in Alzheimer’s Disease

Neurodegenerative Disease Process Mechanism of impairing brain insulin signaling Consequences in relation to brain insulin signaling
Aβ42 toxicity Competes with insulin and reduces affinity of insulin binding to its receptor
AβPP oligomers desensitize and reduce surface expression of insulin receptors
Interferes with PI3K activation of Akt
Disrupts insulin signaling
Impairs insulin stimulated neuronal survival and plasticity
Increases GSK-3β activation and tau hyperphosphorylation
Microvascular disease Cerebral hypoperfusion, hypoxic-ischemic injury Exacerbates insulin resistance;
Oxidative stress DNA damage, lipid peroxidation, fibrillarization of oligomeric tau and Aβ42 Increases neuro-inflammation and pro-inflammatory cytokine inhibition of insulin signaling
Toxic lipids impair signaling through PI3K-Akt
Transition metal ion accumulations Mitochondrial dysfunction, oxidative stress, tau and AβPP oligomer fibrillarization Impairs glucose uptake and utilization, inhibits insulin signaling
Hyperphosphorylated-ubiquitinated tau Increases oxidative stress, promotes neuro-inflammation Enhances insulin resistance

Abbreviations: PI3K= phosphoinositol-3- kinase; GSK-3β = glycogen synthase kinase 3β; AβPP= amyloid-β – precursor protein; Aβ 42=amyloid beta peptide-42 amino acids 1-42 cleavage product

Deficiencies in energy metabolism tipped by inhibition of insulin/IGF signaling increase oxidative stress, mitochondrial dysfunction, and pro-inflammatory cytokine activation [,,]. Oxidative stress leads to increased generation and accumulation of reactive oxygen (ROS) and reactive nitrogen species (RNS) that attack subcellular components and organelles. The resulting chemical modifications, including adducts formed with DNA, RNA, lipids, and proteins, compromise the structural and functional integrity of neurons. Consequences include, loss of cell membrane functions, disruption of the neuronal cytoskeleton with dystrophy and synaptic disconnection, deficits in neurotransmitter function and neuronal plasticity, and perturbation of signal transduction and enzymatic pathways required for energy metabolism, homeostasis, and neuronal survival.

Mitochondrial dysfunction exacerbates electron transport chain function, reducing ATP generation and increasing ROS production. Pro-inflammatory cytokine activation is mediated by neuro-inflammatory responses in microglia and astrocytes. Neuro-inflammation increases oxidative stress, organelle dysfunction, and pro-apoptosis signaling. Moreover, stresses caused by inhibition of insulin/IGF signaling stimulate AβPP gene expression [] and aberrant AβPP cleavage, with attendant increased AβPP-Aβ deposition and toxic fibril formation in the brain [,]. Persistence of oxidative stress leads to constitutive activation of kinases e.g. GSK-3β, that promote aberrant hyper-phosphorylation of tau. Therefore, in AD, oxidative stress and impairments in energy metabolism stemming from brain insulin/IGF resistance quite likely contribute to neuronal loss, AβPP toxicity, tau cytoskeletal pathology, and neuro-inflammation [,,]. The degree to which these abnormalities can be effectively targeted for therapy in AD is actively under investigation.

MECHANISMS OF BRAIN INSULIN/IGF RESISTANCE IN NEURODEGENERATION [FIG. [FIG.33]

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High caloric intake and/or chronic low-level nitrosamine exposures [through diet, smoking, agriculture], promote fatty liver disease (steatohepatitis) that progresses due to injury and inflammation, eventually leading to hepatic insulin resistance. The same poor physiological states also promote obesity, diabetes mellitus, and other peripheral insulin resistance diseases. Toxic lipids, including ceramides, made in the liver, get released into the circulation, cross the blood-brain barrier, and cause brain insulin resistance, inflammation, energy failure, toxicity, and local production of toxic ceramides. The end result is progressive neurodegeneration, including Alzheimer’s disease.

Although aging is clearly the dominant risk factor for AD, growing evidence suggests that peripheral insulin resistance with obesity, T2DM, metabolic syndrome (dyslipidemic states), and non-alcoholic steatohepatitis (NASH) mediate brain insulin/IGF resistance, and thereby contribute to the pathogenesis of mild cognitive impairment (MCI), dementia, and AD [,,,,,,]. However, only within the past several years has this field greatly expanded due to input from both human and experimental animal studies that produced new information about the causes and consequences of brain insulin resistance and deficiency in relation to cognitive impairment [,,,,]. Concerns over the role of peripheral insulin resistance as a mediator of cognitive impairment and sporadic AD have been ratcheted up by globalization of the obesity epidemic [,]. In order to develop logical and novel approaches for treating and preventing neurodegeneration based on the brain insulin resistance hypothesis, three main questions must be addressed: 1) Do T2DM and other peripheral insulin resistance states cause neurodegeneration, including AD? 2) Do T2DM and other peripheral insulin resistance disease states principally serve as co-factors in the pathogenesis of cognitive impairment and neurodegeneration? or 3) Do T2DM and AD fundamentally represent the same disease processes occurring in different target organs and tissues? These questions are addressed below.

Contributions of Obesity and T2DM to Cognitive Impairment and Neurodegeneration

Epidemiologic studies demonstrated that individuals with glucose intolerance, deficits in insulin secretion, or T2DM have a significantly increased risk for developing mild cognitive impairment (MCI) or AD-type dementia. Longitudinal studies provided further evidence that T2DM [,] and obesity/dyslipidemic disorders [] were correlated with later development of MCI, dementia, or AD [,]. However, one study showed that obesity itself, with or without superimposed T2DM, increased the risk for MCI, AD, or other forms of neurodegeneration [], suggesting that systemic factors related to obesity, other than T2DM, can promote neurodegeneration. On the other hand, although a relatively high percentage of individuals with MCI or dementia have T2DM, peripheral insulin resistance, or obesity, the vast majority of patients with AD do not have these diseases. To gain a better understanding of the contributions of T2DM and obesity to neurodegeneration, attention must be given to postmortem human and experimental animal studies.

In general, the arguments made in favor of the concept that T2DM or obesity causes AD are not founded; however, the concept that peripheral insulin resistance disease states contribute to cognitive impairment and AD pathogenesis or progression does have a sound basis. Against a causal role are the findings that, postmortem human brain studies demonstrated no significant increase in AD diagnosis among diabetics [], and similarly abundant densities of senile plaques and rates of neurofibrillary tangle pathology were observed in subjects with T2DM compared with normal aged controls, although peripheral insulin resistance was more common in AD than with normal aging []. Since neurofibrillary tangles and dystrophic neurites are hallmarks of AD and correlate with severity of dementia, the abovementioned findings in human postmortem studies indicate that T2DM alone is not sufficient to cause AD. On the other hand, in experimental mouse and rat models, chronic high fat diet (HFD) feeding and diet induced obesity (DIO) with associated T2DM, do cause cognitive impairment with deficits in spatial learning and memory [,]. Moreover, experimental obesity with T2DM causes mild brain atrophy with brain insulin resistance, neuro-inflammation, oxidative stress, and deficits in cholinergic function [,]. An important qualifier about these studies is that the associated brain abnormalities were typically modest in severity, and they were devoid of the most important structural lesions that characterize AD, i.e. neurofibrillary tangles. Therefore, observations both in humans and experimental models suggest that while obesity or T2DM can be associated with cognitive impairment, mild brain atrophy, and a number of AD-type biochemical and molecular abnormalities in brain, including insulin resistance and oxidative stress, they do not cause significant AD pathology. Instead, the findings suggest that T2DM, obesity, and probably other peripheral/systemic insulin resistance states serve as co-factors contributing to the pathogenesis or progression of neurodegeneration. The significance of these results is that therapeutic strategies designed to treat T2DM, obesity, and systemic insulin resistance could help slow the progress or reduce the severity of AD, but they will not likely prevent it altogether. Correspondingly, a number of studies have already demonstrated that treatment with hypoglycemic or insulin sensitizer agents can be protective in reducing the incidence and severity of AD brain pathology [].

Novo-peridol , dementia , narcotics and heart failure

Haloperidol (Oral route)

Pronunciation:

hal-oh-PER-i-dol

Brand Names:

  • Haldol
  • Alti-Haloperidol
  • Apo-Haloperidol
  • Novo-Peridol
  • Peridol
  • Pms-Haloperidol
  • Ratio-Haloperidol

Dosage Forms:

  • Tablet
  • Solution

Warnings:

Oral route(Tablet)Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Although the causes of death in clinical trials were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that antipsychotic drugs may increase mortality. It is unclear from these studies to what extent the mortality findings may be attributed to the antipsychotic drug as opposed to patient characteristics. Haloperidol is not approved for the treatment of patients with dementia-related psychosis .

Classifications:

Therapeutic—

Antipsychotic

Pharmacologic—

Dopamine Antagonist

Chemical—

Butyrophenone

Uses of This Medicine:

Haloperidol is used to treat nervous, emotional, and mental conditions (eg, schizophrenia). It is also used to control the symptoms of Tourette’s disorder. This medicine should not be used to treat behavior problems in older adult patients who have dementia.

Haloperidol is also used to treat severe behavioral problems (eg, aggressive, impulsive behavior) or hyperactivity in children who have already been treated with psychotherapy or other medicines that did not work well.

This medicine is available only with your doctor’s prescription.

Before Using This Medicine:

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies—

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Children—

Appropriate studies have not been performed on the relationship of age to the effects of haloperidol in children younger than 3 years of age. Safety and efficacy have not been established.

Older adults—

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of haloperidol in the elderly. However, elderly women are more likely to have a side effect called tardive dyskinesia, and elderly patients are more likely to have age-related heart or lung problems, which may require an adjustment in the dose for patients receiving haloperidol.

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Angina (severe chest pain) or
  • Breast cancer, history of or
  • Encephalopathy or
  • Heart or blood vessel disease, severe or
  • Hyperprolactinemia (high prolactin in the blood) or
  • Hypotension (low blood pressure) or
  • Lung or breathing problems (eg, bronchopneumonia) or
  • Mania or
  • Neuroleptic malignant syndrome, history of or
  • Seizures, history of—Use with caution. May make these conditions worse.
  • Central nervous system depression, severe or
  • Coma or
  • Dementia in elderly or
  • Parkinson’s disease—Should not be used in patients with these conditions.
  • Heart rhythm problems (eg, familial long QT-syndrome), history of or
  • Hypokalemia (low potassium in the blood) or
  • Hypomagnesemia (low magnesium in the blood) or
  • Thyroid problems—May increase risk for more serious side effects.
  • ————-

Dopamine agonists play an important role in the regulation of the central nervous-cardiovascular, renal, and hormonal systems through stimulation of dopaminergic (DA1 and DA2) and alpha- and beta-adrenergic receptors. Several studies have shown that in fat and diabetic mice. The aim of the present study was to evaluate the interaction of the dopaminergic and endocrine systems by determining the effect of the dopaminergic antagonist, metoclopramide, and dopamine on insulin secretion and cardiovascular response by blockade and activation of dopamine receptors in healthy and type 2 diabetic subjects. Healthy subjects (n =15) and subjects with type 2 diabetes (n = 15) of both genders, aged 18 to 60 years, were recruited into this study. A comparative experimental design of 90 minutes was performed in which placebo (0.9% saline) was infused intravenously for the first 30 minutes followed by metoclopramide (7.5 microg/kg/min), a dopamine receptor antagonist for 30 minutes, and then metoclopramide (7.5 microg/kg/min) plus dopamine (0.5-3 microg/kg/min) for 30 minutes.

The following clinical and biochemical parameters were measured at the beginning and then every 30 minutes of the experimental period (30′, 60′ and 90′): systolic-diastolic and mean arterial blood pressure, heart rate, serum glucose, insulin, triacylglycerides, and total cholesterol. Baseline glycosylated hemoglobin was measured and homeostasis model assessment for insulin resistance was calculated from insulin and glucose levels. Twelve-lead electrocardiograms were also obtained at these points.

Dopamine infusion induced an increase in serum insulin, systolic blood pressure, and heart rate in healthy subjects but not in subjects with type 2 diabetes. Infusion of metoclopramide induced a hypotensive effect in healthy subjects, which was blunted by inclusion of dopamine in the infusion mixture.

In subjects with diabetes, metoclopramide had no effect on blood pressure, but addition of dopamine raised systolic blood pressure. Neither metoclopramide nor dopamine altered significantly the lipid profile in healthy or diabetic subjects.

Dopaminergic drugs increase serum insulin probably by interacting with dopaminergic receptors, but stimulation of beta-adrenergic receptors cannot be ruled out. Stimulation of cardiovascular dopamine receptors also caused modifications of hemodynamic parameters in healthy subjects, but apparently these receptors are attenuated in patients with type 2 diabetes probably as a result of endothelial dysfunction and alterations in the sympathetic nervous system sensitivity.


Connie’s comments: If my father who has diabetes and dementia at 98 falls with a hairline hip fracture, I will not put him on narcotics for a long period of time.

Brain and insulin

Image shows a brain.

BRAIN SWITCH TELLS BODY TO BURN FAT AFTER A MEAL

Researchers report the brain’s ability to sense insulin and coordinate feeding with energy expenditure is controlled by a mechanism that is turned on after fasting to inhibit insulin response and conserve energy. After feeding, the mechanism is turned off to facilitate insulin response and expend energy. However, in obese people, researchers believe the switch may stay on all the time.  READ MORE…

Insulin Resistance May Lead to Faster Cognitive Decline

Insulin Resistance May Lead to Faster Cognitive Decline

Summary: A new study reports insulin resistance is linked to accelerated cognitive decline.

Source: AFTAU.

Executive function and memory are particularly vulnerable to the effects of insulin resistance, Tel Aviv University researchers say.

A new Tel Aviv University study published in the Journal of Alzheimer’s Disease finds that insulin resistance, caused in part by obesity and physical inactivity, is also linked to a more rapid decline in cognitive performance. According to the research, both diabetic and non-diabetic subjects with insulin resistance experienced accelerated cognitive decline in executive function and memory.

The study was led jointly by Prof. David Tanne and Prof. Uri Goldbourt and conducted by Dr. Miri Lutski, all of TAU’s Sackler School of Medicine.

“These are exciting findings because they may help to identify a group of individuals at increased risk of cognitive decline and dementia in older age,” says Prof. Tanne. “We know that insulin resistance can be prevented and treated by lifestyle changes and certain insulin-sensitizing drugs. Exercising, maintaining a balanced and healthy diet, and watching your weight will help you prevent insulin resistance and, as a result, protect your brain as you get older.”

Image shows an Insulin bottle and needle.

A two-decade study

Insulin resistance is a condition in which cells fail to respond normally to the hormone insulin. The resistance prevents muscle, fat, and liver cells from easily absorbing glucose. As a result, the body requires higher levels of insulin to usher glucose into its cells. Without sufficient insulin, excess glucose builds up in the bloodstream, leading to prediabetes, diabetes, and other serious health disorders.

The scientists followed a group of nearly 500 patients with existing cardiovascular disease for more than two decades. They first assessed the patients’ baseline insulin resistance using the homeostasis model assessment (HOMA), calculated using fasting blood glucose and fasting insulin levels. Cognitive functions were assessed with a computerized battery of tests that examined memory, executive function, visual spatial processing, and attention. The follow-up assessments were conducted 15 years after the start of the study, then again five years after that.

The study found that individuals who placed in the top quarter of the HOMA index were at an increased risk for poor cognitive performance and accelerated cognitive decline compared to those in the remaining three-quarters of the HOMA index. Adjusting for established cardiovascular risk factors and potentially confounding factors did not diminish these associations.

“This study lends support for more research to test the cognitive benefits of interventions such as exercise, diet, and medications that improve insulin resistance in order to prevent dementia,” says Prof. Tanne. The team is currently studying the vascular and non-vascular mechanisms by which insulin resistance may affect cognition.

ABOUT THIS NEUROLOGY RESEARCH ARTICLE

Source: George Hunka – AFTAU 
Image Source: NeuroscienceNews.com image is adapted from the AFTAU press release.
Original Research: Abstract for “Insulin Resistance and Future Cognitive Performance and Cognitive Decline in Elderly Patients with Cardiovascular Disease” by Lutski, Miri; Weinstein, Galit; Goldbourt, Uri; and Tanne, David in Journal of Alzheimer’s Disease. Published online March 21 2017 doi:10.3233/JAD-161016

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AFTAU “Insulin Resistance May Lead to Faster Cognitive Decline.” NeuroscienceNews. NeuroscienceNews, 23 March 2017.
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Abstract

Insulin Resistance and Future Cognitive Performance and Cognitive Decline in Elderly Patients with Cardiovascular Disease

Background: The role of insulin resistance (IR) in the pathogenesis of cognitive performance is not yet clear. Objective: To examine the associations between IR and cognitive performance and change in cognitive functions two decades later in individuals with cardiovascular disease with and without diabetes.

Methods: A subset of 489 surviving patients (mean age at baseline 57.7±6.5 y) with coronary heart disease who previously participated in the secondary prevention Bezafibrate Infarction Prevention (BIP trial; 1990–1997), were included in the current neurocognitive study. Biochemical parameters including IR (using the homeostasis model of assessment; HOMA-IR) were measured at baseline. During 2004–2008, computerized cognitive assessment and atherosclerosis parameters were measured (T1; n = 558; mean age 72.6±6.4 years). A second cognitive assessment was performed during 2011–2013 (T2; n = 351; mean age 77.2±6.4 years). Cognitive function, overall and in specific domains, was assessed. We used linear regression models and linear mixed models to evaluate the differences in cognitive performance and decline, respectively.

Results: Controlling for potential confounders, IR (top HOMA-IR quartile versus others) was associated with subsequent poorer cognitive performance overall (β= –4.45±Standard Error (SE) 1.54; p = 0.004) and on tests of memory and executive function among non-diabetic patients (β= –7.16±2.38; p = 0.003 and β= –3.33±1.84; p = 0.073, respectively). Moreover, among non-diabetic patients, IR was related to a greater decline overall (β= –0.17±0.06; p = 0.008), and in memory (β= –0.22±0.10; p = 0.024) and executive function (β= –0.19±0.08; p = 0.012). The observed associations did not differ after excluding subjects with prevalent stroke or dementia.

Conclusion: IR is related to subsequent poorer cognitive performance and greater cognitive decline among patients with cardiovascular disease with and without diabetes.

“Insulin Resistance and Future Cognitive Performance and Cognitive Decline in Elderly Patients with Cardiovascular Disease” by Lutski, Miri; Weinstein, Galit; Goldbourt, Uri; and Tanne, David in Journal of Alzheimer’s Disease. Published online March 21 2017 doi:10.3233/JAD-161016

Physical inactivity, dopamine, lactate , glucose and aging

aging exerAfter 96 years of age, he has crying spells in the afternoon or early evening hours when our brain hormones are slowing down to ready for sleep.  With less exercise and more time sitting down watching TV and eating every 2 hours, he forgets to remember things as his brain and muscles are not working as it should when he was young.  Whenever I see him, I give him a hug and trains other caregivers to hug him more. He perks up and can do more walking.

Hugging can increase the production of dopamine in your brain, and this can be seen in PET scans of the brain. Dopamine levels are low in people with conditions like Parkinsonism and mood disorders like Depression.

So if you see someone depressed, give him a hug, and bring a little joy to their life.
Dopamine levels are low to those with Alzheimer and Parkinson’s diseases.
Dopamine containing neurons control  voluntary movements. The association with a physiologically reduced glutamate release from frontal and prefrontal cortices, hippocampi and amygdala would induce further decrease of Dopamine release, inducing hypo-activity, gait disturbances and decline of executive functions.

The earlier the impairment of Dopamine system occurs, the fastest the cognitive decline goes.

Hormones and nuerotransmitters dopamine, norepinephrine and epinephrine are responsible for our emotions and affects our memory and muscles causing Alzheimer and Parkinson’s disease.
In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons (nerve cells) to send signals to other nerve cells. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior.
Epinephrine, also called adrenaline, hormone that is secreted mainly by the medulla of the adrenal glands and that functions primarily to increase cardiac output and to raise glucose levels in the blood.
Norepinephrine, also called noradrenaline, substance that is released predominantly from the ends of sympathetic nerve fibers and that acts to increase the force of skeletal muscle contraction and the rate and force of contraction of the heart.

Supplements and Nutrition

Eat happy foods: eggs, colorful whole foods and yams and whole foods/dietary supplements rich in the following nutrients:
Folate, Vitamin B complex, SAM-E,omega 3, digestive enzymes, probiotic, Vitamin C, copper, iron from greens, NAC
Suggested exercises should include walking, dancing , stretching, yoga, meditation, and other body movement.
Remember all the above information assumes that you have a healthy liver. Take care of the laboratory organ of your body, the liver which processes all chemicals, drugs, alcohol and nutrition in your body.
During sleep, your brain is helping the liver detox your body. The lymphatic system which travels opposite your circulatory system is responsible for cleaning your blood.

Lactate and brain

Lactate is considered an important metabolite in the human body, but there has been considerable debate about its roles in brain function. Research in recent years has suggested that lactate from astrocytes may be crucial for supporting axonal function, especially during times of high metabolic demands or hypoglycemia. The astrocyte-neuron lactate transfer shuttle system serves a protective function to ensure a supply of substrates for brain metabolism, and oligodendrocytes appear to also influence availability of lactate. There is increasing evidence for lactate acting as a signaling molecule in the brain to link metabolism, substrate availability, blood flow and neuronal activity.
The brain produces its own lactate from the metabolism of glycogen and tends to export lactate at rest []. Lactate is brought into the brain across the BBB to be used as fuel when plasma lactate is high or plasma glucose is low [].

Klotho enzyme , calcium, insulin , Vitamin D and Alzheimer

Klotho is an enzyme that in humans is encoded by the KL gene.[5]

This gene encodes a type-I membrane protein that is related to β-glucuronidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing, bone loss and alcohol consumption.[6][7]Transgenic mice that overexpress Klotho live longer than wild-type mice.[8]

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Function

Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in aging. Its discovery was documented in 1997 by Kuro-o et al.[9] The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology.

The Klotho protein is a novel β-glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,[10][11] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[12]

The binding of certain fibroblast growth factors (FGF’s) viz., FGF19, FGF20, and FGR23, to their Fibroblast growth factor receptors, is promoted by their interaction with Klotho.[13]

Klotho-deficient mice manifest a syndrome resembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endothelium dependent vasodilation and impaired angiogenesis, suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived NO production.

Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice.[8] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations.[14]

The mechanism of action of klotho is not fully understood, but it changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 and decreasing that of TRPC6.[15] Additionally, klotho increases membrane expression of the inward rectifier channel ROMK.[15]

Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes.

Because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants.

These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities (hypervitaminosis).