Agent Orange Herbicidal Toxin-Initiation of Alzheimer-Type Neurodegeneration.

Background: Agent Orange (AO) is a Vietnam War-era herbicide that contains a 1 : 1 ratio of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Emerging evidence suggests that AO exposures cause toxic and degenerative pathologies that may increase the risk for Alzheimer's disease (AD). Objective: This study investigates the effects of the two main AO constituents on key molecular and biochemical indices of AD-type neurodegeneration. Methods: Long Evans rat frontal lobe slice cultures treated with 250µg/ml of 2,4-D, 2,4,5-T, or both (D + T) were evaluated for cytotoxicity, oxidative injury, mitochondrial function, and AD biomarker expression. Results: Treatment with the AO constituents caused histopathological changes corresponding to neuronal, white matter, and endothelial cell degeneration, and molecular/biochemical abnormalities indicative of cytotoxic injury, lipid peroxidation, DNA damage, and increased immunoreactivity to activated Caspase 3, glial fibrillary acidic protein, ubiquitin, tau, paired-helical filament phosphorylated tau, AßPP, Aß, and choline acetyltransferase. Nearly all indices of cellular injury and degeneration were more pronounced in the D + T compared with 2,4-D or 2,4,5-T treated cultures. Conclusions: Exposures to AO herbicidal chemicals damage frontal lobe brain tissue with molecular and biochemical abnormalities that mimic pathologies associated with early-stage AD-type neurodegeneration. Additional research is needed to evaluate the long-term effects of AO exposures in relation to aging and progressive neurodegeneration in Vietnam War Veterans.

Agent Orange Causes Metabolic Dysfunction and Molecular Pathology Reminiscent of Alzheimer's Disease.

Background: Agent Orange, an herbicide used during the Vietnam War, contains 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Agent Orange has teratogenic and carcinogenic effects, and population-based studies suggest Agent Orange exposures lead to higher rates of toxic and degenerative pathologies in the peripheral and central nervous system (CNS). Objective: This study examines the potential contribution of Agent Orange exposures to neurodegeneration. Methods: Human CNS-derived neuroepithelial cells (PNET2) treated with 2,4-D and 2,4,5-T were evaluated for viability, mitochondrial function, and Alzheimer's disease (AD)-related proteins. Results: Treatment with 250µg/ml 2,4-D or 2,4,5-T significantly impaired mitochondrial function, caused degenerative morphological changes, and reduced viability in PNET2 cells. Correspondingly, glyceraldehyde-3-phosphate dehydrogenase expression which is insulin-regulated and marks the integrity of carbohydrate metabolism, was significantly inhibited while 4-hydroxy-2-nonenal, a marker of lipid peroxidation, was increased. Tau neuronal cytoskeletal protein was significantly reduced by 2,4,5-T, and relative tau phosphorylation was progressively elevated by 2,4,5-T followed by 2,4-D treatment relative to control. Amyloid-ß protein precursor (AßPP) was increased by 2,4,5-T and 2,4-D, and 2,4,5-T caused a statistical trend (0.05 < p<0.10) increase in Aß. Finally, altered cholinergic function due to 2,4,5-T and 2,4-D exposures was marked by significantly increased choline acetyltransferase and decreased acetylcholinesterase expression, corresponding with responses in early-stage AD. Conclusion: Exposures to Agent Orange herbicidal chemicals rapidly damage CNS neurons, initiating a path toward AD-type neurodegeneration. Additional research is needed to understand the permanency of these neuropathologic processes and the added risks of developing AD in Agent Orange-exposed aging Vietnam Veterans.

Concordant and Discordant Cerebrospinal Fluid and Plasma Cytokine and Chemokine Responses in Mild Cognitive Impairment and Early-Stage Alzheimer's Disease.

Neuroinflammation may be a pathogenic mediator and biomarker of neurodegeneration at the boundary between mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD). Whether neuroinflammatory processes are endogenous to the central nervous system (CNS) or originate from systemic (peripheral blood) sources could impact strategies for therapeutic intervention. To address this issue, we measured cytokine and chemokine immunoreactivities in simultaneously obtained lumbar puncture cerebrospinal fluid (CSF) and serum samples from 39 patients including 18 with MCI or early AD and 21 normal controls using a 27-plex XMAP bead-based enzyme-linked immunosorbent assay (ELISA). The MCI/AD combined group had significant (p < 0.05 or better) or statistically trend-wise (0.05 ≤ p ≤ 0.10) concordant increases in CSF and serum IL-4, IL-5, IL-9, IL-13, and TNF-α and reductions in GM-CSF, b-FGF, IL-6, IP-10, and MCP-1; CSF-only increases in IFN-y and IL-7 and reductions in VEGF and IL-12p70; serum-only increases in IL-1ß, MIP-1α, and eotaxin and reductions in G-CSF, IL-2, IL-8 and IL-15; and discordant CSF-serum responses with reduced CSF and increased serum PDGF-bb, IL-17a, and RANTES. The results demonstrate simultaneously parallel mixed but modestly greater pro-inflammatory compared to anti-inflammatory or neuroprotective responses in CSF and serum. In addition, the findings show evidence that several cytokines and chemokines are selectively altered in MCI/AD CSF, likely corresponding to distinct neuroinflammatory responses unrelated to systemic pathologies. The aggregate results suggest that early management of MCI/AD neuroinflammation should include both anti-inflammatory and pro-neuroprotective strategies to help prevent disease progression.

Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer's Disease (Type 3 Diabetes).

Malignant brain aging corresponds to accelerated age-related declines in brain functions eventually derailing the self-sustaining forces that govern independent vitality. Malignant brain aging establishes the path toward dementing neurodegeneration, including Alzheimer's disease (AD). The full spectrum of AD includes progressive dysfunction of neurons, oligodendrocytes, astrocytes, microglia, and the microvascular systems, and is mechanistically driven by insulin and insulin-like growth factor (IGF) deficiencies and resistances with accompanying deficits in energy balance, increased cellular stress, inflammation, and impaired perfusion, mimicking the core features of diabetes mellitus. The underlying pathophysiological derangements result in mitochondrial dysfunction, abnormal protein aggregation, increased oxidative and endoplasmic reticulum stress, aberrant autophagy, and abnormal post-translational modification of proteins, all of which are signature features of both AD and dysregulated insulin/IGF-1-mechanistic target of rapamycin (mTOR) signaling. This article connects the dots from benign to malignant aging to neurodegeneration by reviewing the salient pathologies associated with initially adaptive and later dysfunctional mTOR signaling in the brain. Effective therapeutic and preventive measures must be two-pronged and designed to 1) address complex and shifting impairments in mTOR signaling through the re-purpose of effective anti-diabetes therapeutics that target the brain, and 2) minimize the impact of extrinsic mediators of benign to malignant aging transitions, e.g., inflammatory states, obesity, systemic insulin resistance diseases, and repeated bouts of general anesthesia, by minimizing exposures or implementing neuroprotective measures.

Post-Polio Syndrome Revisited.

Post-polio syndrome (PPS) is characterized by recrudescence or worsening of motor neuron disease symptoms decades after recovery from acute paralytic poliovirus infection, i.e., poliomyelitis. PPS afflicts between 25% and 40% of poliomyelitis survivors and mimics motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS), due to its selective impairment, degeneration, or death of motor neurons in the brainstem and spinal cord. Herein, we report a case of PPS in a 68-year-old man with a remote history of bulbar and cervical cord involvement by poliomyelitis, review the relevant literature, and contrast the salient histopathologic features that distinguish our case of PPS from ALS.

Differential Early Mechanistic Frontal Lobe Responses to Choline Chloride and Soy Isoflavones in an Experimental Model of Fetal Alcohol Spectrum Disorder.

Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of neurodevelopmental defects, and white matter is a major target of ethanol neurotoxicity. Therapeutic interventions with choline or dietary soy could potentially supplement public health preventive measures. However, since soy contains abundant choline, it would be important to know if its benefits are mediated by choline or isoflavones. We compared early mechanistic responses to choline and the Daidzein+Genistein (D+G) soy isoflavones in an FASD model using frontal lobe tissue to assess oligodendrocyte function and Akt-mTOR signaling. Long Evans rat pups were binge administered 2 g/Kg of ethanol or saline (control) on postnatal days P3 and P5. P7 frontal lobe slice cultures were treated with vehicle (Veh), Choline chloride (Chol; 75 µM), or D+G (1 µM each) for 72 h without further ethanol exposures. The expression levels of myelin oligodendrocyte proteins and stress-related molecules were measured by duplex enzyme-linked immunosorbent assays (ELISAs), and mTOR signaling proteins and phosphoproteins were assessed using 11-plex magnetic bead-based ELISAs. Ethanol's main short-term effects in Veh-treated cultures were to increase GFAP and relative PTEN phosphorylation and reduce Akt phosphorylation. Chol and D+G significantly modulated the expression of oligodendrocyte myelin proteins and mediators of insulin/IGF-1-Akt-mTOR signaling in both control and ethanol-exposed cultures. In general, the responses were more robust with D+G; the main exception was that RPS6 phosphorylation was significantly increased by Chol and not D+G. The findings suggest that dietary soy, with the benefits of providing complete nutrition together with Choline, could be used to help optimize neurodevelopment in humans at risk for FASD.

A diagnosis of Birt-Hogg-Dubé syndrome in individuals with Smith-Magenis syndrome: Recommendation for cancer screening.

We report a series of four unrelated adults with Smith-Magenis syndrome (SMS) and concomitant features of Birt-Hogg-Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.

Associations of early life stress with leptin and ghrelin in healthy young adults.

BACKGROUND: Childhood adversity is a major risk factor for cardiometabolic health problems. Stress-related changes in diet suggest a role for endocrine factors that influence dietary intake, such as leptin and ghrelin. These hormones influence metabolism and may contribute to the relationship of early adversity, mental, and cardiometabolic health. This study examined levels of leptin and ghrelin in a sample of young adults with and without early life stress (ELS). METHODS: Young adults ages 18-40 (N = 200; 68.5% female) were recruited from the community. Participants with ELS (N = 118) had childhood maltreatment, and a subset, n = 92 (78.0%) also had parental loss, and n = 65 (55.1%) also had a current psychiatric disorder. Control participants (N = 82) had no maltreatment, parental loss, or psychiatric disorders. Standardized interviews and self-reports assessed demographics, adversity, medical/psychiatric history, and health behaviors. Exclusion criteria included medical conditions and current medications other than hormonal contraceptives. Body Mass Index (BMI) and other anthropometrics were measured, and fasting plasma was assayed for total ghrelin and leptin with the Bio-Plex Pro Human Diabetes Panel. RESULTS: While ELS was significantly associated with greater leptin (r = .16, p = .025), a finding which held when adjusted for age and sex (F(3196)= 28.32, p = .011), this relationship was abolished when accounting for BMI (p = .44). Participants with ELS also had significantly lower total ghrelin (r = .21, p = .004), which held adjusting for age and sex (p = .002) and was attenuated (p = .045) when the model included BMI (F=46.82, p < .001). Current psychiatric disorder was also a significant predictor of greater leptin (r = .28, p < .001) and lower ghrelin (r = .29, p = .003). In the model with ELS and covariates, psychiatric disorder remained significant (F=7.26, p = .008) and ELS was no longer significant (p = .87). Associations with severity and recent perceived stress were also examined. CONCLUSION: The relationship of ELS and leptin was no longer significant when accounting for BMI, suggesting potential avenues for intervention. Ghrelin findings persisted after correction for BMI, which may be secondary to physiological differences in the regulation of these hormones (leptin is produced by adipocytes, whereas ghrelin is produced primarily in the GI tract). Lastly, these findings suggest that psychiatric functioning may be a key component contributing to the relationship of lower total ghrelin and childhood adversity.

Tissue Microarray Lipidomic Imaging Mass Spectrometry Method: Application to the Study of Alcohol-Related White Matter Neurodegeneration.

Central nervous system (CNS) white matter pathologies accompany many diseases across the lifespan, yet their biochemical bases, mechanisms, and consequences have remained poorly understood due to the complexity of myelin lipid-based research. However, recent advances in matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) have minimized or eliminated many technical challenges that previously limited progress in CNS disease-based lipidomic research. MALDI-IMS can be used for lipid identification, semi-quantification, and the refined interpretation of histopathology. The present work illustrates the use of tissue micro-arrays (TMAs) for MALDI-IMS analysis of frontal lobe white matter biochemical lipidomic pathology in an experimental rat model of chronic ethanol feeding. The use of TMAs combines workload efficiency with the robustness and uniformity of data acquisition. The methods described for generating TMAs enable simultaneous comparisons of lipid profiles across multiple samples under identical conditions. With the methods described, we demonstrate significant reductions in phosphatidylinositol and increases in phosphatidylcholine in the frontal white matter of chronic ethanol-fed rats. Together with the use of a novel rapid peak alignment protocol, this approach facilitates reliable inter- and intra-group comparisons of MALDI-IMS data from experimental models and could be extended to human disease states, including using archival specimens.

Dietary Soy Prevents Alcohol-Mediated Neurocognitive Dysfunction and Associated Impairments in Brain Insulin Pathway Signaling in an Adolescent Rat Model.

BACKGROUND: Alcohol-related brain degeneration is linked to cognitive-motor deficits and impaired signaling through insulin/insulin-like growth factor type 1 (IGF-1)-Akt pathways that regulate cell survival, plasticity, metabolism, and homeostasis. In addition, ethanol inhibits Aspartyl-asparaginyl-ß-hydroxylase (ASPH), a downstream target of insulin/IGF-1-Akt signaling and an activator of Notch networks. Previous studies have suggested that early treatment with insulin sensitizers or dietary soy could reduce or prevent the long-term adverse effects of chronic ethanol feeding. OBJECTIVE: The goal of this study was to assess the effects of substituting soy isolate for casein to prevent or reduce ethanol's adverse effects on brain structure and function. METHODS: Young adolescent male and female Long Evans were used in a 4-way model as follows: Control + Casein; Ethanol + Casein; Control + Soy; Ethanol + Soy; Control = 0% ethanol; Ethanol = 26% ethanol (caloric). Rats were fed isocaloric diets from 4 to 11 weeks of age. During the final experimental week, the Morris Water maze test was used to assess spatial learning (4 consecutive days), after which the brains were harvested to measure the temporal lobe expression of the total phospho-Akt pathway and downstream target proteins using multiplex bead-based enzyme-linked immunosorbent assays (ELISAs) and duplex ELISAs. RESULTS: Ethanol inhibited spatial learning and reduced brain weight, insulin signaling through Akt, and the expression of ASPH when standard casein was provided as the protein source. The substitution of soy isolate for casein largely abrogated the adverse effects of chronic ethanol feeding. In contrast, Notch signaling protein expression was minimally altered by ethanol or soy isolate. CONCLUSIONS: These novel findings suggest that the insulin sensitizer properties of soy isolate may prevent some of the adverse effects that chronic ethanol exposure has on neurobehavioral function and insulin-regulated metabolic pathways in adolescent brains.

Myriocin Treatment Reverses Alcohol-Induced Alterations in Polyunsaturated Fatty Acid-Containing Phospholipid Expression in the Liver.

Chronic heavy alcohol exposure causes steatohepatitis manifested by abnormal intra-hepatocyte accumulation of lipid and parenchymal inflammation. Attendant alterations in polyunsaturated fatty acid (PUFA)-containing phospholipids could cause alcoholic liver disease (ALD) to progress by promoting oxidative stress, inflammation, and fibrogenesis. Previously we showed that myriocin, a serine palmitoyltransferase inhibitor, ameliorates experimental alcohol-induced steatohepatitis. However, the surprising overall therapeutic responses suggested that myriocin's targets may go beyond sphingolipids. To this end, the present study examines the effects of myriocin on hepatic composition of docosahexaenoic acid (DHA)- and arachidonic acid (AA)-containing phospholipids in an experimental model of ALD. A chronic+binge ethanol exposure model was generated by feeding Long Evans rats with ethanol-containing diets (24% caloric content) for 8 weeks and simultaneously binge gavage administering 2 g/kg ethanol on Tuesdays, Thursdays and Saturdays during Weeks 6-8. Myriocin was administered by i.p. injection on Mondays, Wednesdays, and Fridays of Weeks 3-8. Control rats were studied in parallel. Upon euthanasia, the livers were harvested to examine ethanol- and/or myriocin-modulation of hepatic lipids using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). Results were analyzed statistically by two-way analysis of variance and depicted with data bar plots and heatmaps. Chronic+binge ethanol exposures significantly increased hepatic expression of AA-containing phospholipids including PE(36:4) (P = .005), PE(38:4) (P = .03), and PI(38:4) (P = .04) and reduced DHA-containing phospholipids including PS(40:6) (P = .03) and PE(40:6) (P = .04) relative to control. Myriocin partially reversed ethanol's effects on hepatic PUFA expression by decreasing PE(36:4) (P = .004) and increasing PS(40:6) (P = .04) and PI(40:6) (P = .0003) relative to ethanol-exposed rats. Ethanol-mediated alterations in hepatic PUFA-containing phospholipids may contribute to hepatic oxidative and inflammatory injury by increasing AA and fibrogenesis by inhibiting DHA. The results suggest that Myriocin may help reduce or prevent long-term and progressive liver injury stemming from excessive chronic+binge ethanol consumption.

Agent Orange Reviewed: Potential Role in Peripheral Neuropathy and Neurodegeneration.

Agent Orange, a dioxin-containing toxin, was used as an herbicide during the Vietnam War. Exposures to Agent Orange were initially linked to birth defects among Vietnamese civilians residing near aerially sprayed regions. Years later, returning South Korean and U.S. Veterans exposed to Agent Orange exhibited increased rates of malignancy, cardiovascular disease, diabetes and birth defects in their offspring. Growing evidence that herbicides and pesticides contribute to chronic diseases including neurodegeneration raises concern that Agent Orange exposures may have increased the risk for later development of peripheral or central nervous system (CNS) degeneration. This article reviews published data on the main systemic effects and the prevalence rates, relative risks, characteristics and correlates of Agent Orange-associated peripheral neuropathy and CNS dementia-associated diseases. The critical findings were that relatively high levels of Agent Orange exposure increased risk of developing peripheral neuropathy either alone or as a co-factor complication of diabetes mellitus and likely contributed to the pathogenesis of CNS degenerative diseases, including Alzheimer's, Parkinson's and vascular dementias. Given the protracted intervals between the Agent Orange exposures and disease emergence, additional research is needed to identify mechanistic correlates of the related neurological disorders, including lifestyle co-factors.

Therapeutic Effects of Myriocin in Experimental Alcohol-Related Neurobehavioral Dysfunction and Frontal Lobe White Matter Biochemical Pathology.

Background & Objective: Chronic excessive alcohol consumption causes white matter degeneration with myelin loss and impaired neuronal conductivity. Subsequent rarefaction of myelin accounts for the sustained deficits in cognition, learning, and memory. Correspondingly, chronic heavy or repeated binge alcohol exposures in humans and experimental models alter myelin lipid composition leading to build-up of ceramides which can be neurotoxic and broadly inhibitory to brain functions. Methods: This study examined the effects of chronic + binge alcohol exposures (8 weeks) and intervention with myriocin, a ceramide inhibitor, on neurobehavioral functions (Open Field, Novel Object Recognition, and Morris Water Maze tests) and frontal lobe white matter myelin lipid biochemical pathology in an adult Long-Evans rat model. Results: The ethanol-exposed group had significant deficits in executive functions with increased indices of anxiety and impairments in spatial learning acquisition. Myriocin partially remediated these effects of ethanol while not impacting behavior in the control group. Ethanol-fed rats had significantly smaller brains with broadly reduced expression of sulfatides and reduced expression of two of the three sphingomyelins detected in frontal white matter. Myriocin partially resolved these effects corresponding with improvements in neurobehavioral function. Conclusion: Therapeutic strategies that support cerebral white matter myelin expression of sulfatide and sphingomyelin may help remediate cognitive-behavioral dysfunction following chronic heavy alcohol consumption in humans.

The Differential Effects of Chronic Alcohol and Cigarette Smoke Exposures on Cognitive-Behavioral Dysfunction in Long Evans Rats.

Background and Objective: Chronic heavy alcohol consumption and daily cigarette smoking are the most prevalent substance use problems in the U.S., including Veterans. Excessive alcohol use causes neurocognitive and behavioral deficits that can be linked to neurodegeneration. Similarly, preclinical and clinical data suggest that smoking also leads to brain atrophy. This study examines the differential and additive effects of alcohol and cigarette smoke (CS) exposures on cognitive-behavioral function. Methods: A 4-way experimental model of chronic alcohol and CS exposures was generated using 4-week-old male and female Long Evans rats that were pair-fed with Lieber-deCarli isocaloric liquid diets containing 0% or 24% ethanol for 9 weeks. Half of the rats in the control and ethanol groups were exposed to CS for 4 hours/day and 4 days/week for 9 weeks. All rats were subjected to Morris Water Maze, Open Field, and Novel Object Recognition testing in the last experimental week. Results: Chronic alcohol exposure impaired spatial learning as shown by significantly increased latency to locate the platform, and it caused anxiety-like behavior marked by the significantly reduced percentage of entries to the center of the arena. Chronic CS exposure impaired recognition memory as suggested by significantly less time spent at the novel object. Combined exposures to alcohol and CS did not show any significant additive or interactive effect on cognitive-behavioral function. Conclusion: Chronic alcohol exposure was the main driver of spatial learning, while the effect of secondhand CS exposure was not robust. Future studies need to mimic direct CS exposure effects in humans.

Heterogeneous Longitudinal Antibody Responses to Covid-19 mRNA Vaccination.

BACKGROUND: Public health measures to stem the coronavirus disease 2019 (COVID-19) pandemic are challenged by social, economic, health status, and cultural disparities that facilitate disease transmission and amplify its severity. Prior pre-clinical biomedical technologic advances in nucleic acid-based vaccination enabled unprecedented speed of conceptualization, development, production, and widespread distribution of mRNA vaccines that target SARS-CoV-2's Spike (S) protein. DESIGN: Twenty-five female and male volunteer fulltime employees at the Providence VA Medical Center participated in this study to examine longitudinal antibody responses to the Moderna mRNA-1273 vaccine. IgM-S and IgG-S were measured in serum using the Abbott IgM-S-Qualitative and IgG2-S-Quantitative chemiluminescent assays. RESULTS: Peak IgM responses after Vaccine Dose #1 were delayed in 6 (24%) and absent in 7 (28%) participants. IgG2-S peak responses primarily occurred 40 to 44 days after Vaccine Dose #1, which was also 11 to 14 days after Vaccine Dose #2. However, subgroups exhibited Strong (n = 6; 24%), Normal (n = 13; 52%), or Weak (n = 6; 24%) peak level responses that differed significantly from each other (P < .005 or better). The post-peak IgG2-S levels declined progressively, and within 6 months reached the mean level measured 1 month after Vaccine Dose #1. Weak responders exhibited persistently low levels of IgG2-S. Variability in vaccine responsiveness was unrelated to age or gender. CONCLUSION: Host responses to SARS-CoV-2-Spike mRNA vaccines vary in magnitude, duration and occurrence. This study raises concern about the lack of vaccine protection in as many as 8% of otherwise normal people, and the need for open dialog about future re-boosting requirements to ensure long-lasting immunity via mRNA vaccination versus natural infection.

Dysregulation of Insulin-Linked Metabolic Pathways in Alzheimer's Disease: Co-Factor Role of Apolipoprotein E ɛ4.

BACKGROUND: Brain insulin resistance and deficiency are well-recognized abnormalities in Alzheimer's disease (AD) and likely mediators of impaired energy metabolism. Since apolipoprotein E (APOE) is a major risk factor for late-onset AD, it was of interest to examine its potential contribution to altered insulin-linked signaling networks in the brain. OBJECTIVE: The main goal was to evaluate the independent and interactive contributions of AD severity and APOE ɛ4 dose on brain expression of insulin-related polypeptides and inflammatory mediators of metabolic dysfunction. METHODS: Postmortem fresh frozen frontal lobe tissue from banked cases with known APOE genotypes and different AD Braak stages were used to measure insulin network polypeptide immunoreactivity with a commercial multiplex enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant AD Braak stage and APOE genotype-related abnormalities in insulin, C-peptide, gastric inhibitory polypeptide (GIP), glucaton-like peptide-1 (GLP-1), leptin, ghrelin, glucagon, resistin, and plasminogen activator inhibitor-1 (PAI-1) were detected. The main factors inhibiting polypeptide expression and promoting neuro-inflammatory responses included AD Braak stage and APOE ɛ4/ɛ4 rather than ɛ3/ɛ4. CONCLUSION: This study demonstrates an expanded role for impaired expression of insulin-related network polypeptides as well as neuroinflammatory mediators of brain insulin resistance in AD pathogenesis and progression. In addition, the findings show that APOE has independent and additive effects on these aberrations in brain polypeptide expression, but the impact is decidedly greater for APOE ɛ4/ɛ4 than ɛ3/ɛ4.

Betel Quid Health Risks of Insulin Resistance Diseases in Poor Young South Asian Native and Immigrant Populations.

Betel quid, traditionally prepared with areca nut, betel leaf, and slaked lime, has been consumed for thousands of years, mainly in the form of chewing. Originally used for cultural, medicinal, and ceremonial purposes mainly in South Asian countries, its use has recently spread across the globe due to its psychoactive, euphoric, and aphrodisiac properties. Now it is widely used as a social lubricant and source of financial profit. Unfortunately, the profit motive has led to high rates of habitual consumption with eventual conversion to addiction among young girls and boys. Moreover, the worrisome practice of including tobacco in quid preparations has grown, particularly among pregnant women. Major health concerns include increased rates of malignancy, oral pathology, and cardiovascular, hepatic, fertility, metabolic, and neuropsychiatric disorders. Metabolic disorders and insulin resistance disease states such as type 2 diabetes, obesity, and metabolic syndrome contribute to cognitive decline and neurodegeneration. Mechanistically, the constituents of areca nut/betel quid are metabolized to N-nitroso compounds, i.e., nitrosamines, which are carcinogenic at high doses and cause insulin resistance following chronic low-level exposures. From an epidemiological perspective, the rising tide of insulin resistance diseases including obesity, diabetes, and dementias that now disproportionately burden poor countries has been propagated by rapid commercialization and enhanced access to betel quid. Public health measures are needed to impose socially and ethically responsible barriers to yet another cause of global health disparity.

Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing.

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.

Critical Shifts in Cerebral White Matter Lipid Profiles After Ischemic-Reperfusion Brain Injury in Fetal Sheep as Demonstrated by the Positive Ion Mode MALDI-Mass Spectrometry.

Ischemic-reperfusion (I/R) injury to cerebral white matter during the perinatal period leads to long-term cognitive and motor disabilities in children. Immature white matter oligodendrocytes are especially vulnerable to metabolic insults such as those caused by hypoxic, ischemic, and reperfusion injury. Consequences include an impaired capacity of oligodendrocytes to generate and maintain mature lipid-rich myelin needed for efficient neuronal conductivity. Further research is needed to increase an understanding of the early, possibly reversible myelin-associated pathologies that accompany I/R white matter injury. This experiment characterized I/R time-dependent alterations in cerebral white matter lipid profiles in an established fetal sheep model. Fetal sheep (127 days gestation) were subjected to 30 min of bilateral carotid artery occlusion followed by 4 h (n = 5), 24 h (n = 7), 48 h (n = 3), or 72 h (n = 5) of reperfusion, or sham treatment (n = 5). Supraventricular cerebral white matter lipids were analyzed using the positive ionization mode matrix-assisted laser desorption/ionization mass spectrometry. Striking I/R-associated shifts in phospholipid (PL) and sphingolipid expression with a prominent upregulation of cardiolipin, phosphatidylcholine, phosphatidylinositol monomannoside, sphingomyelin, sulfatide, and ambiguous or unidentified lipids were observed to occur mainly at I/R-48 and normalized or suppressed responses at I/R-72. In fetal sheep, cerebral I/R caused major shifts in white matter myelin lipid composition favoring the upregulated expression of diverse PLs and sphingolipids which are needed to support neuronal membrane, synaptic, metabolic, and cell signaling functions.

Ontogeny of inter-alpha inhibitor protein (IAIP) expression in human brain.

Inter-alpha inhibitor proteins (IAIPs) are naturally occurring immunomodulatory molecules found in most tissues. We have reported ontogenic changes in the expression of IAIPs in brain during development in sheep and abundant expression of IAIPs in fetal and neonatal rodent brain in a variety of cellular types and brain regions. Although a few studies identified bikunin, light chain of IAIPs, in adult human brain, the presence of the complete endogenous IAIP protein complex has not been reported in human brain. In this study, we examined the immunohistochemical expression of endogenous IAIPs in human cerebral cortex from early in development through the neonatal period and in adults using well-preserved postmortem brains. We examined total, nuclear, and cytoplasmic staining of endogenous IAIPs and their expression in neurofilament light polypeptide-positive neurons and glial fibrillary acidic protein (GFAP)-positive astrocytes. IAIPs were ubiquitously detected for the first time in cerebral cortical cells at 24-26, 27-28, 29-36, and 37-40 weeks of gestation and in adults. Quantitative analyses revealed that IAIPs were predominately localized in the nucleus in all age groups, but cytoplasmic IAIP expression was more abundant in adult than in the younger ages. Immunoreactivity of IAIPs was expressed in neurons and astrocytes in all age groups. In addition, IAIP co-localization with GFAP-positive astrocytes was more abundant in adults than in the developing brain. We conclude that IAIPs exhibit ubiquitous expression, and co-localize with neurons and astrocytes in the developing and adult human brain suggesting a potential role for IAIPs in development and endogenous neuroprotection.