Biomedical subjects

Thomas J Montine

Publications and source records attributed to Thomas J Montine.

At least 19 recordsLinked to original sources

PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗

PubMed2006

Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice.

BACKGROUND: Inheritance of the three different alleles of the human apolipoprotein (apo) E gene (APOE) are associated with varying risk or clinical outcome from a variety of neurologic diseases. ApoE isoform-specific modulation of several pathogenic processes, in addition to amyloid beta metabolism in Alzheimer's disease, have been proposed: one of these is innate immune response by glia. Previously we have shown that primary microglia cultures from targeted replacement (TR) APOE mice have apoE isoform-dependent innate immune activation and paracrine damage to neurons that is greatest with TR by the epsilon4 allele (TR APOE4) and that derives from p38 mitogen-activated protein kinase (p38MAPK) activity. METHODS: Primary cultures of TR APOE2, TR APOE3 and TR APOE4 astrocytes were stimulated with lipopolysaccharide (LPS). ApoE secretion, cytokine production, and nuclear factor-kappa B (NF-kappaB) subunit activity were measured and compared. RESULTS: Here we showed that activation of primary astrocytes from TR APOE mice with LPS led to TR APOE-dependent differences in cytokine secretion that were greatest in TR APOE2 and that were associated with differences in NF-kappaB subunit activity. CONCLUSION: Our results suggest that LPS activation of innate immune response in TR APOE glia results in opposing outcomes from microglia and astrocytes as a result of TR APOE-dependent activation of p38MAPK or NF-kappaB signaling in these two cell types.

Journal Article↗

PubMed2006

Neurotoxicity from innate immune response is greatest with targeted replacement of E4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK.

Inheritance of APOE alleles is associated with varying clinical outcomes in several neurodegenerative diseases that are associated with innate immune response in brain. We tested the hypothesis that inheritance of different APOE alleles would significantly modulate neurotoxicity arising from glial innate immune response. We first used dissociated cultures of wild-type (wt) murine neurons and glia derived from mice with targeted replacement (TR) of the epsilon2, epsilon3, or, epsilon4 APOE allele. Our results showed that the vast majority of bystander damage to wt neurons derived from microglia was greatest with TR APOE4 glia, intermediate from TR APOE3 glia, and least from TR APOE2 glia and preceded detectable NO secretion. Microglial p38MAPK-dependent cytokine secretion followed a similar pattern of TR APOE dependence. In hippocampal slice cultures, innate immune activation had a similar pattern of TR APOE-dependence and produced postsynaptic neuronal damage in TR APOE4 and TR APOE3 but not TR APOE2 cultures that was p38MAPK dependent. These findings suggest a new mechanism by which inheritance of different APOE alleles may influence the outcome of neurodegenerative diseases associated with microglial innate immune response.

Alleles↗

PubMed2006

Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice.

Oxidative stress may play a key role in Alzheimer's disease (AD) neuropathology. Here, the effects of the antioxidant, alpha-lipoic acid (ALA) were tested on the Tg2576 mouse, a transgenic model of cerebral amyloidosis associated with AD. Ten-month old Tg2576 and wild type mice were fed an ALA-containing diet (0.1%) or control diet for 6 months and then assessed for the influence of diet on memory and neuropathology. ALA-treated Tg2576 mice exhibited significantly improved learning, and memory retention in the Morris water maze task compared to untreated Tg2576 mice. Twenty-four hours after contextual fear conditioning, untreated Tg2576 mice exhibited significantly impaired context-dependent freezing. ALA-treated Tg2576 mice exhibited significantly more context freezing than the untreated Tg2576 mice. Assessment of brain soluble and insoluble beta-amyloid levels revealed no differences between ALA-treated and untreated Tg2576 mice. Brain levels of nitrotyrosine, a marker of nitrative stress, were elevated in Tg2576 mice, while F2 isoprostanes and neuroprostanes, oxidative stress markers, were not elevated in the Tg2576 mice relative to wild type. These data indicate that chronic dietary ALA can reduce hippocampal-dependent memory deficits of Tg2576 mice without affecting beta-amyloid levels or plaque deposition.

Aging↗

PubMed2006

PGH2-derived levuglandin adducts increase the neurotoxicity of amyloid beta1-42.

The body of evidence indicating that oligomers of amyloid beta(1-42) (Abeta(1-42)) produce toxicity to neurons, together with our demonstration that prostaglandin H(2) (PGH(2)) oligomerizes amyloid beta(1-42), led to the examination of the neurotoxicity of amyloid beta(1-42) treated with PGH(2). The neurotoxic effects of Abeta(1-42) incubated with PGH(2) was examined in primary cultures of cerebral neurons of mice, monitoring the reduction of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of cell toxicity. Whereas Abeta(1-42) itself, incubated for 24 h, has little or no effect on MTT reduction, Abeta(1-42) 24 h after exposure to PGH(2) produced a marked inhibition of MTT reduction, comparable with the inhibition resulting from Abeta(1-42) that has been oligomerized by incubation for 6 days. Similar results were obtained when Abeta(1-42) was incubated with levuglandin E(2) (LGE(2)), a reactive aldehyde formed by spontaneous rearrangement of PGH(2). The oligomers formed from reaction of Abeta(1-42) with LGE(2) exhibit immunochemical similarity with amyloid-derived diffusible ligands (ADDLs), as determined by analysis of the products of reaction of Abeta(1-42) with LGE(2) using western blotting with an antibody that is selective for ADDLs.

Amyloid beta-Peptides↗

PubMed2006

Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype.

BACKGROUND: The origin and significance of Lewy bodies and neurites (Lewy body pathology [LBP]) in Alzheimer disease (AD) are poorly understood. OBJECTIVE: To examine LBP in the brainstem, limbic cortex, and neocortex of a large number of familial AD cases with mutations in 2 presenilin (PSEN) genes. METHODS: Twenty-five familial AD cases with 9 known PSEN 1 mutations and 14 familial AD cases with a single PSEN 2 mutation (N141I) were examined for LBP using alpha-synuclein immunohistochemistry and sampling of multiple brainstem and cortical regions. RESULTS: The amygdala was the most vulnerable site for LBP. In fact, virtually all (24 [96%] of 25 cases) of the PSEN 1 mutation cases had LBP in the amygdala. The PSEN 1 mutation cases also had more frequent LBP in the amygdala and neocortex than those with the PSEN 2 mutation. However, within families with a single mutation of either PSEN 1 or PSEN 2, there was frequent variability of the LBP. CONCLUSION: These findings suggest that there are genetic influences on the presence of LBP in familial AD as demonstrated by the differences between PSEN 1 and PSEN 2 mutation cases.

Adult↗

PubMed2006

Liquid chromatography with tandem mass spectrometry-based proteomic discovery in aging and Alzheimer's disease.

Systems biology offers enormous potential to understand the complexity of human brain aging and neurodegenerative diseases. Proteomics has an important role in these investigations because of its unique strengths and because of the potential central pathogenic contribution of pathological protein to several of these diseases. Here we have reviewed the methods and presented some examples of liquid chromatography-electrospray ionization-tandem mass spectrometry-based proteomics, with and without quantification using isotope-coded affinity tags, in the investigation of aging and Alzheimer's disease. As protocols and methods for improved quantitative high-throughput proteomics constantly improve, this approach will likely continue to provide deeper insight into human brain aging and neurodegenerative diseases.

Aging↗

PubMed2006

Characterization of proteome of human cerebrospinal fluid.

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Adult↗

PubMed2006

Selectively increased oxidative modifications mapped to detergent-insoluble forms of Abeta and beta-III tubulin in Alzheimer's disease.

Deleterious post-translational modifications (PTMs) to the neuronal cytoskeleton are a proposed mechanistic link between accumulation of amyloid (A) beta peptides and subsequent abnormalities of tau and neurodegeneration in Alzheimer's disease (AD). Here we tested the hypothesis that PTMs on neuronal tubulins selectively accumulate in a pathological protein fraction in AD. We used new software, P-MOD, to identify comprehensively and map PTMs using mass spectral data from soluble (normal) and detergent-insoluble (pathological) protein fractions from AD, as well as total extracts from controls, for selected proteins: Abeta, tau, apolipoprotein (apo) E, glial fibrillary acidic protein (GFAP), alpha-III tubulin, and beta-III tubulin. Our results confirmed direct observations of others by identifying methionine (M) sulfoxides at Abeta position 35 and numerous sites of tau phosphorylation in detergent-insoluble protein from AD, while no PTMs were enriched on primarily astrocyte-derived apoE or GFAP in this fraction. P-MOD mapped several abundant M sulfoxides to neuron-enriched beta-III tubulin but not its heterodimeric partner, neuron-enriched alpha-III tubulin, a result confirmed by selective suppression of CNBr-mediated cleavage of beta-III tubulin. These findings are the first comprehensive assessment of PTMs in AD and point to oxidative modification of beta-III tubulin as a potential contributor to the neuronal cytoskeletal disruption that is characteristic of AD.

Alzheimer Disease↗

PubMed2006

Lewy body pathology in late-onset familial Alzheimer's disease: a clinicopathological case series.

BACKGROUND: Lewy body pathology (LBP) is a common finding in Alzheimer's disease (AD), but the pathophysiology for this coexistent pathology remains unclear. METHODS: We ascertained late-onset dementia (mean age > 60 years old) families with at least 3 autopsies. We then conducted systematic alpha-synuclein (SNCA) immunostaining to determine the frequency and distribution of LBP in families with late-onset AD. RESULTS: All 32 subjects met NIA-Reagan neuropathological criteria for "high likelihood" of having AD. Hematoxylin and eosin staining detected LBP in the substantia nigra (SN) in 8 (25%) individuals. SNCA immunostaining detected LBP in 21 individuals (66%). While all subjects with SN LBP had co-existent amygdala LBP, many (9/21, 43%) of the cases with amygdala LBP did not have coexistent SN LBP (McNemar's chi-square test, p=0.008). Each family had at least two cases with LBP, but no family had LBP in all autopsied cases. CONCLUSIONS: Presence of significant AD pathology in one family member was highly predictive of similar pathology in other family members. However, despite the use of more sensitive SNCA immunohistochemistry, the presence of LBP was variable within all 7 families. Consistent with previous studies in sporadic and familial AD, the amygdala appeared to be the most vulnerable region for LBP in AD. Additional clinical, neuropathologic, and genetic studies are necessary to determine the clinical and pathological significance of LBP in AD.

Age of Onset↗

PubMed2006

Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders.

Biomarkers are needed to assist in the diagnosis and medical management of various neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy body (DLB). We have employed a multiplex quantitative proteomics method, iTRAQ (isobaric Tagging for Relative and Absolute protein Quantification), in conjunction with multidimensional chromatography, followed by tandem mass spectrometry (MS/MS), to simultaneously measure relative changes in the proteome of cerebrospinal fluid (CSF) obtained from patients with AD, PD, and DLB compared to healthy controls. The diagnosis of AD and DLB was confirmed by autopsy, whereas the diagnosis of PD was based on clinical criteria. The proteomic findings showed quantitative changes in AD, PD, and DLB as compared to controls; among more than 1,500 identified CSF proteins, 136, 72, and 101 of the proteins displayed quantitative changes unique to AD, PD, and DLB, respectively. Eight unique proteins were confirmed by Western blot analysis, and the sensitivity at 95% specificity was calculated for each marker alone and in combination. Several panels of unique makers were capable of distinguishing AD, PD and DLB patients from each other as well as from controls with high sensitivity at 95% specificity. Although these preliminary findings must be validated in a larger and different population of patients, they suggest that a roster of proteins may be generated and developed into specific biomarkers that could eventually assist in clinical diagnosis and monitoring disease progression of AD, PD and DLB.

Alzheimer Disease↗

PubMed2005

Faster plasma vitamin E disappearance in smokers is normalized by vitamin C supplementation.

Vitamin E disappearance is accelerated in cigarette smokers due to their increased oxidative stress and is inversely correlated with plasma vitamin C concentrations. Therefore, we hypothesized that ascorbic acid supplementation (500 mg, twice daily; 2 weeks) would normalize smokers' plasma alpha- and gamma-tocopherol disappearance rates and conducted a double-blind, placebo-controlled, randomized crossover investigation in smokers (n=11) and nonsmokers (n=13) given a single dose of deuterium-labeled alpha- and gamma-tocopherols (50 mg each d6-RRR-alpha and d2-RRR-gamma-tocopheryl acetate). During the placebo trial, smokers, compared with nonsmokers, had significantly (P<0.05) greater alpha- and gamma-tocopherol fractional disappearance rates and shorter half-lives. Ascorbic acid supplementation doubled (P<0.0001) plasma ascorbic acid concentrations in both groups and attenuated smokers', but not nonsmokers', plasma alpha- and gamma-tocopherol (P<0.05) fractional disappearance rates by 25% and 45%, respectively. Likewise, smokers' plasma deuterium-labeled alpha- and gamma-tocopherol concentrations were significantly higher (P<0.05) at 72 h during ascorbic acid supplementation compared with placebo. Ascorbic acid supplementation did not significantly change (P>0.05) time of maximal or maximal-labeled alpha- and gamma-tocopherol concentrations. Smokers' plasma F2alpha-isoprostanes were approximately 26% higher than nonsmokers (P>0.05) and were not affected by ascorbic acid supplementation in either group (P>0.05). In summary, cigarette smoking increased plasma alpha- and gamma-tocopherol fractional disappearance rates, suggesting that the oxidative stress from smoking oxidizes tocopherols and that plasma ascorbic acid reduces alpha- and gamma-tocopheroxyl radicals to nonoxidized forms, thereby decreasing vitamin E disappearance in humans.

Administration, Oral↗

PubMed2005

Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer's disease.

Epidemiological studies demonstrate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in normal aging populations reduces the risk of developing Alzheimer's disease (AD). NSAIDs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2, which catalyze the first committed step in the synthesis of prostaglandins. These studies implicate COX-mediated inflammation as an early and potentially reversible preclinical event; however, the mechanism by which COX activity promotes development of AD has not been determined. Recent studies implicate the prostaglandin E2 (PGE2) E prostanoid subtype 2 (EP2) receptor in the development of the innate immune response in brain. Here, we report that deletion of the PGE2 EP2 receptor in the APPSwe-PS1DeltaE9 model of familial AD results in marked reductions in lipid peroxidation in aging mice. This reduction in oxidative stress is associated with significant decreases in levels of amyloid-beta (Abeta) 40 and 42 peptides and amyloid deposition. Aged APPSwe-PS1DeltaE9 mice lacking the EP2 receptor harbor lower levels of beta C-terminal fragments, the product of beta-site APP cleaving enzyme (BACE1) processing of amyloid precursor protein. Increases in BACE1 processing have been demonstrated in models of aging and AD and after oxidative stress. Our results indicate that PGE2 signaling via the EP2 receptor promotes age-dependent oxidative damage and increased Abeta peptide burden in this model of AD, possibly via effects on BACE1 activity. Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD, and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD.

Alzheimer Disease↗

PubMed2005

Lack of beta-methylamino-l-alanine in brain from controls, AD, or Chamorros with PDC.

High levels of beta-methylamino-l-alanine (BMAA), a putative neurotoxin, have been reported in brain samples from Chamorros and patients with Alzheimer disease (AD) from western Canada. The authors assayed free BMAA in the brains of five control subjects and five patients with AD from the US Pacific Northwest as well as Chamorros with and without Parkinson-dementia complex. In contrast to others, they detected no free BMAA in any of these samples.

Aged↗

PubMed2005

Proteomic determination of widespread detergent-insolubility including Abeta but not tau early in the pathogenesis of Alzheimer's disease.

Biochemical characterization of the major detergent-insoluble proteins that comprise hallmark histopathologic lesions initiated the molecular era of Alzheimer's disease (AD) research. Here, we reinvestigated detergent-insoluble proteins in AD using modern proteomic techniques. Using liquid chromatography (LC)-mass spectrometry (MS)-MS-based proteomics, we robustly identified 125 proteins in the detergent-insoluble fraction of late-onset AD (LOAD) temporal cortex that included several proteins critical to Abeta production, components of synaptic scaffolding, and products of genes linked to an increased risk of LOAD; we verified 15 of 15 of these proteins by Western blot. Following multiple analyses, we estimated that these represent ~80% of detergent-insoluble proteins in LOAD detectable by our method. Abeta, tau, and 7 of 8 other newly identified detergent-insoluble proteins were disproportionately increased in temporal cortex from patients with LOAD and AD derived from mutations in PSEN1 and PSEN2; all of these except tau were elevated in individuals with prodromal dementia, while none except Abeta were elevated in aged APPswe mice. These results are consistent with the amyloid hypothesis of AD and extend it to include widespread protein insolubility, not exclusively Abeta insolubility, early in AD pathogenesis even before the onset of clinical dementia.

Alzheimer Disease↗

PubMed2005

Prostaglandin H(2)-derived adducts of proteins correlate with Alzheimer's disease severity.

The formation of cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive gamma-ketoaldehydes, levuglandin (LG) E(2) and LGD(2). These gamma-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.

Aged↗

PubMed2005

Suppression of murine cerebral F2-isoprostanes and F4-neuroprostanes from excitotoxicity and innate immune response in vivo by alpha- or gamma-tocopherol.

Oxidative damage to brain is a featured shared by several destructive and degenerative diseases and is thought to contribute to disease pathogenesis. Two commonly proposed sources of the increased free radical stress that leads to oxidative damage in several of these diseases are excitotoxicity and activation of innate immunity, both of which are proposed pharmacologic targets. Here we used models of excitotoxicity, intracerebroventricular (ICV) kainate (KA), and innate immune activation, ICV lipopolysaccharide (LPS), to test the effectiveness of peripherally administered alpha-tocopherol (AT) and gamma-tocopherol (GT) as neuroprotectants. We quantified murine cerebral oxidative damage by measuring F(2)-isoprostanes (IsoPs) and F(4)-neuroprostanes (NeuroPs) using stable isotope dilution methods followed by gas chromatography-mass spectrometry with selective ion monitoring. Our data showed that peripherally administered AT and GT were equally effective at suppressing acute oxidative damage from direct excitotoxicity caused by KA. In contrast, peripherally administered AT, but not GT, was effective at suppressing delayed neuronal oxidative damage from activated glial innate immune response. These data imply that AT may be more broadly protective of cerebrum from oxidative damage in different disease contexts.

Animals↗

PubMed2005

Mechanisms of 4-hydroxynonenal-induced neuronal microtubule dysfunction.

We have previously demonstrated that neuronal microtubules are exquisitely sensitive to the lipid peroxidation product 4-hydroxynonenal (HNE). The mechanism, however, by which HNE disrupts the microtubules, is not known. Sulfhydryl groups of protein-cysteines constitute main targets of HNE. Indeed, HNE is mainly detoxified by conjugation to glutathione (GSH), a reaction that leads to depletion of cellular GSH. GSH maintains protein sulfhydryl groups in the reduced form and has been implicated in the regulation of cytoskeletal function. Here, we assess what role depletion of cellular GSH plays in the HNE-induced microtubule disruption. We demonstrate that HNE and its intracellularly activated tri-ester analog, HNE(Ac)(3), cause substantial GSH depletion in Neuro2A cells. However, other compounds inducing GSH depletion had no effect on the microtubule network. Therefore, HNE-induced depletion of cellular GSH does not contribute to the HNE-induced microtubule disruption. We previously demonstrated that another main cellular target of HNE is tubulin, the core protein of microtubules containing abundant cysteines. The functional relevance of this adduction, however, had not been evaluated. Here, we demonstrate that exposure of Neuro 2A cells to HNE or HNE(Ac)(3) results in the inhibition of cytosolic taxol-induced tubulin polymerization. These and our previous observations strongly support the hypothesis that HNE-adduction to tubulin is the primary mechanism involved in the HNE-induced loss of the highly dynamic neuronal microtubule network.

Aldehydes↗