Brain repair diet

Do follow the anti-parasitic diet, eat whole foods rich in Vitamin C , A and E and get sufficient night time sleep. Avoid and run away from toxic people. Stay with nature and meet new friends. Make someone happy.  In nursing facilities, some seniors are suffering from sundowning syndrome, a state of acute mental confusion and behavioral change that takes place at the end of the day and into the night.  Since we synthesize cholesterol at night, eat a healthy fat food at night and use ways to calm the body for a good night sleep (dim the lights , except for a hallway night light) and stay with the seniors until he goes to sleep.


Omega-3 Fatty Acids, Vitamin E, Curcumin, and Caffeine

A number of studies point to the healthy effects of dietary factors on the brain. For example, fish-derived omega-3 fatty acids have been shown to improve cognition, plasticity, and recovery of neurons after traumatic brain injury. One of the most important forms of omega-3 fatty acids, docosahexaenoic acid (DHA), has been found to be a key component of neuronal membranes at sites of signal transduction at the synapse, suggesting that its action is vital to brain structure and function []. Evidence suggests that DHA serves to improve neuronal function by supporting synaptic membrane fluidity and function, and regulating gene expression and cell signaling []. Because the human body is not capable of producing its own DHA, supplementation of diet with foods rich in DHA is important in insuring proper function of neurons and in facilitating neuronal recovery after injury []. An additional benefit of omega-3 fatty acids which we observed in our studies is that they appear to reduce oxidative stress damage that results from trauma, indicating at the possibility of their application in assisting the recovery process [].

Another dietary supplement that has shown promise in protecting neurons is Vitamin E, found in certain oils, nuts, and spinach. Vitamin E functions as an antioxidant, reducing free radicals in the brain which would otherwise impede optimal function of neurons. Vitamin E has shown positive effects on memory performance in older people [], indicating its ability to maintain neuronal health. A different study similarly revealed the benefits of Vitamin E by showing a correlation between the amount of ingested Vitamin E and improved neurological performance, survival, and brain mitochondrial function in aging mice [].

Curcumin, a yellow curry spice, has also been suggested to enhance recovery events after brain trauma, displaying particular potency in preserving cognition. Curcumin was found to improve neuronal function in individuals afflicted with Alzheimer’s disease by reducing oxidative stress and amyloid pathology []. In addition, it was found to protect the brain from lipid peroxidation [] and nitric oxide-based radicals []. In accordance with these observations, our own studies have showed that the supplementation of curcumin into the diets of rats reduced the effects of experimental concussive injury on cognitive function tasks [].

Studies observing the effects of caffeine on neuronal regeneration and function are recently emerging. A new study shows that chronic, but not acute, treatment with caffeine protects the brain against injury in animal models of Parkinson’s disease and stroke by increasing glutamate release and inflammatory cytokine production [].

Caloric Intake

Cognition and plasticity of the brain have also been shown to be affected by caloric intake and the frequency of food consumption. Restriction of calories seems to increase levels of BDNF, resulting in improved neuronal function. Fasting every other day has been shown to protect neurons in the hippocampus against excitotoxicity-induced death []. In the study, rats put on an every-other-day-fasting diet for 2-4 months had hippocampus neurons that were much more resistant to degeneration induced by kainic acid, and greater preserved memory than rats fed ad lib.

Saturated-Fat Diet

While certain foods seem to contribute positively to neuronal health, diets that are rich in saturated fats appear to decrease levels of BDNF in the brain and lead in poorer neuronal performance. Molteni and colleagues have shown that rats fed a diet high in saturated fats and refined sugars (similar in content to the “junk food” that has become popular today) for a period of 1-2 months, performed significantly worse on the spatial learning mater maze test than rats fed a healthier diet that was low in fat and contained complex carbohydrates [].


Depriving Deadly Brain Tumors Of Cholesterol , parasites need cholesterol

Depriving Deadly Brain Tumors Of Cholesterol May Be Their Achilles’ Heel

Summary: Depriving glioblastoma brain cancer cells of cholesterol caused tumor regression and prolonged survival in mouse models of the disease, a new study reports.

Source: UCSD.

In mouse models, alternative approach proves promising against hard-to-treat cancer.

Researchers at University of California San Diego School of Medicine, Ludwig Institute for Cancer Research and The Scripps Research Institute, with colleagues in Los Angeles and Japan, report that depriving deadly brain cancer cells of cholesterol, which they import from neighboring healthy cells, specifically kills tumor cells and caused tumor regression and prolonged survival in mouse models.

The findings, published in the online October 13 issue of Cancer Cell, also present a potential alternative method for treating glioblastomas (GBM), the most common and most aggressive form of brain cancer. GBMs are extremely difficult to treat. The median survival rate is just over 14 months, with few treated patients living five years or more past diagnosis.

Adult brain cancers are almost universally fatal, in part because of the biochemical composition of the central nervous system (CNS) and the blood-brain barrier, which selectively and protectively limits the passage of molecules from the body into the brain, but which also blocks most existing chemotherapies, contributing to treatment failure.

This includes blocking small molecule inhibitors that target growth factor receptors, which have not proven to be effective with brain cancers, possibly due to their inability to get past the blood-brain barrier and achieve sufficiently high levels in the central nervous system.

“Researchers have been thinking about ways to deal with this problem,” said senior author Paul S. Mischel, MD, a member of the Ludwig Cancer Research branch at UC San Diego and professor in the UC San Diego School of Medicine Department of Pathology. “We have been challenged by the fact that GBMs are among the most genomically-well characterized forms of cancer, with clear evidence of targetable driver oncogene mutations but this information has yet to benefit patients, at least in part, because the drugs designed to target these oncogenes have difficulty accessing their targets in the brain. We have been trying to find an alternative way to use this information to develop more effective treatments.

“One such approach stems from the observation that oncogenes (mutated genes) can rewire the biochemical pathways of cells in ways that make them dependent on proteins that are not themselves encoded by oncogenes. Targeting these ‘oncogene-induced co-dependencies’ opens up a much broader pharmacopeia, including the use of drugs that aren’t traditionally part of cancer drug pipelines but have better pharmacological properties.”

In previous research, Mischel and others had noted GBM cells cannot synthesize cholesterol, which is vital to cell structure and function, particularly in the brain. Instead, GBM cells derive what they need from brain cells called astrocytes, which produce cholesterol in abundance. Roughly 20 percent of total body cholesterol is found in the brain.

When normal cells have sufficient cholesterol, they convert some of it into molecules called oxysterols, which activate a receptor in the cell’s nucleus — the liver X receptor (LXR) — to shut down the uptake of cholesterol.

“So when normal cells get enough cholesterol, they stop making it, stop taking it up and start pumping it out,” said Mischel. “We found that in GBM cells, this mechanism is completely disrupted. They’re like parasites of the brain’s normal cholesterol system. They steal cholesterol and don’t have an off switch. They just keep gobbling the stuff up.”

Image shows an MRI brain scan of a glioblastoma patient.

GBM cells ensure their cholesterol supply by suppressing the production of oxysterols, the researchers said, ensuring cells’ LXRs remain inactive.

The research team, including Andrew Shaiu and Tim Gahman of Ludwig’s Small Molecule Development team at UC San Diego, identified an experimental metabolic disease drug candidate named LXR-623 that activates LXRs.

In mouse models, LXR-623 easily crossed the blood-brain barrier to bind with LXRs in normal cells, stimulating the production of oxysterols and the reduction of cholesterol. There was no effect upon healthy neurons and other brain cells, the scientists found, but GBM cells were deprived of vital cholesterol, resulting in cell death and tumor regression.

“Disrupting cholesterol import by GBM cells caused dramatic cancer cell death and shrank tumors significantly, prolonging the survival of the mice,” said Mischel. “The strategy worked with every single GBM tumor we looked at and even on other types of tumors that had metastasized to the brain. LXR-623 also had minimal effect on astrocytes or other tissues of the body.”

Mischel suggested the GBM strategy could be implemented in clinical trials using drug-candidates under development or in early trials.


Co-authors of this paper include: first author Genaro R. Villa, Yuchao Gu, Xin Rong, Cynthia Hong, Timothy F. Cloughesy, UCLA; Jonathan J. Hulce, Kenneth M. Lum, Michael Martini and Benjamin F. Cravatt, TSRI; Ciro Zanca, Junfeng Bi, Shiro Ikegami, Gabrielle L. Cahill, Huijun Yang, Kristen M. Turn, Feng Liu, Gary C. Hon, David Jenkins, Aaron M. Armando, Oswald Quehenberger, Frank B. Furnari, and Webster K. Cavenee, UC San Diego; and Kenta Masui and Peter Tontonoz, Tokyo Women’s Medical University.

Funding: Funding for this research came, in part, from the National Cancer Institute (F31CA186668), the National Institute for Neurological Diseases and Stroke (NS73831, NS080939), the Defeat GBM Program of the National Brain Tumor Society, the Ben and Catherine Ivy Foundation, the Ziering Family Foundation and the National Institutes of Health (CA132630).

Source: Scott LaFee – UCSD
Image Source: image is credited A. Christaras.
Original Research: The study will appear in Cancer Cell.

All parasites may be metabolising cholesterol

The requirement of cholesterol for internalization of eukaryotic pathogens like protozoa (Leishmaniasis, Malaria and Toxoplasmosis) and the exchange of cholesterol along with other metabolites during reproduction in Schistosomes (helminths) under variable circumstances are poorly understood. In patients infected with some other helminthes, alterations in the lipid profile have been observed. Also, the mechanisms involved in lipid changes especially in membrane proteins related to parasite infections remain uncertain. Present review of literature shows that parasites induce significant changes in lipid parameters, as has been shown in the in vitro study where substitution of serum by lipid/cholesterol in medium and in experimental models (in vivo). Thus changes in lipid profile occur in patients having active infections with most of the parasites. Membrane proteins are probably involved in such reactions. All parasites may be metabolising cholesterol, but the exact relationship with pathogenic mechanism is not clear. So far, studies suggest that there may be some factors or enzymes, which allow the parasite to breakup and consume lipid/cholesterol.


Essential oils, smell, brain, healing

Connie b. Dellobuono
Connie b. Dellobuono, Health author and blogger at , student of nurse midwifery

Most inhaled oils can have psychoactive properties since they are electrically charged chemicals and the brain is also charged.


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


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 [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” [,].


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.


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.


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 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.


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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 [].


the surgeon looking at a scan

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