Alzheimer Disease: Montine TJ

Shie FS, Nivison M, Hsu PC, Montine TJ. · Division of Mental Health and Substance Abuse Research, National Health Research Institutes, No.35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, R.O.C. · Curr Med Chem. · Pubmed #19199928 No free full text.

Abstract: Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Although the etiology of AD remains unclear, microglia-mediated neuroinflammation is believed to play an important role in its pathogenesis. Microglial activation occurs in AD and is characterized by apparent phagocytic activity and by increased production and secretion of several cytokines, chemokines, reactive oxygen and nitrogen species, prostaglandin (PG)E2, and neurotrophic factors. Microglial activation can be neuroprotective through the release of neurotrophic factors and by phagocytosing Abeta, a critical neurotoxic component in AD brain. Concurrently, microglial activation causes elevated inflammatory responses that lead to paracrine damage to neurons. Therefore, a well-controlled microglial activation that diminishes microglial-mediated oxidative damage while promoting neuronal protection may be the key for AD therapy. Peroxisome proliferator-activated receptor gamma (PPARgamma) has recently gained increasing attention in AD due to its function as a molecular target for non-steroidal anti-inflammatory drugs (NSAIDs). In this review, we will discuss the role of PPARgamma in microglial innate immunity in AD and how pharmacological manipulation of microglial activation using PPARgamma ligands might facilitate the treatment of AD.

Sonnen JA, Breitner JC, Lovell MA, Markesbery WR, Quinn JF, Montine TJ. · Department of Pathology and of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. · Free Radic Biol Med. · Pubmed #18482592 links to  free full text

Abstract: Advances in our understanding of the etiologies and pathogenesis of Alzheimer's disease (AD) highlight a role for free radical-mediated injury to brain regions from early stages of this illness. Here we will review the evidence from transgenic mouse models of AD, autopsy samples, and human biofluids obtained during life paying particular attention to the stage of disease. In addition, we will review the epidemiologic literature that addresses the potential of anti-oxidants to prevent incident dementia from AD, and the clinical trial literature that addresses anti-oxidant preventative or therapeutic strategies for different stage of AD. Future efforts in preclinical models and ultimately clinical trials are needed to define optimally effective agents and combinations, doses, and timing to suppress safely this facet of AD.

Picklo MJ, Montine TJ. · Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, Grand Forks, ND 58203, USA. · J Alzheimers Dis. · Pubmed #17917163 links to  free full text

Abstract: Mitochondria play a pivotal role in the life and death of cells and likely contribute importantly to the initiation or progression of many neurodegenerative disorders. Brain is especially vulnerable to lipid peroxidation because of its enrichment in polyunsaturated fatty acids relative to other organs. Multiple studies demonstrate the elevation of numerous lipid peroxidation products and ensuing lipid-derived carbonyls in Alzheimer's disease. In this review, we examine the data describing the effects of lipid-derived carbonyls such as 4-hydroxy-trans-2-nonenal (HNE) and acrolein upon the function of brain mitochondria as well as review the detoxification routes of these carbonyls. From these data, we show that the physical-chemical properties of these carbonyls influence their effects on mitochondria and that multiple essential mitochondrial functions are altered by these endogenous reactive carbonyls. Lastly, we examine the role of mitochondrial aldehyde detoxification pathways and their potential role in the development of AD.

Montine TJ, Quinn J, Kaye J, Morrow JD. · Department of Pathology, University of Washington, Seattle, WA 98104, USA. · J Mol Neurosci. · Pubmed #17901555 No free full text.

Abstract: Alzheimer's disease (AD) is a syndrome caused by a few uncommon mutations that lead to early-onset disease, occurs in adults with Down's syndrome, but is by far most commonly seen as a late-onset disease with multiple risk factors but no causative factors yet identified. Emerging data suggests a chronic disease model for AD with latency, prodrome, and dementia stages together lasting decades. Free radical damage to lipids in brain is one pathogenic process of AD that may be quantified with F(2)-isoprostanes (IsoPs). Whereas brain and cerebrospinal fluid (CSF) F(2)-IsoPs are reproducibly elevated in AD patients at both dementia and prodromal stages of disease, plasma and urine F(2)-IsoPs are not reproducibly increased in AD patients. CSF F(2)-IsoPs may be used to assist in diagnosis and aid in objective assessment of disease progression and response to therapeutics in patients with AD.

Sonnen JA, Keene CD, Montine KS, Li G, Peskind ER, Zhang J, Montine TJ. · Department of Pathology, University of Washington, Seattle, WA 98104-2499, USA. · Expert Rev Neurother. · Pubmed #17678497 No free full text.

Abstract: The development and validation of biomarkers for the latent, prodromal and dementia stages of Alzheimer's disease (AD) is a pressing issue because of their high prevalence and an emerging set of experimental therapeutics that will soon force decisions regarding risk versus benefit. While genetic risk factors and neuroimaging will certainly have important roles to play, here we have focused on biomarkers assayed in body fluids. There is developing consensus for a central role for cerebrospinal fluid amyloid-beta (Abeta)42 and tau species to aid in the diagnosis of AD at different stages; plasma-based assays for Abeta species show some promise, but the picture is much less clear than in the cerebrospinal fluid. Biomarkers of different pathogenic steps thought to contribute to AD will also be important in assessing pharmacologic mechanisms of new therapies. Discovery approaches now underway may develop novel panels of biomarkers for AD. The next 5 years will see standardization of more established approaches, and the combination of different modalities into the most effective means for assessing different stages of AD.

Montine TJ, Woltjer RL, Pan C, Montine KS, Zhang J. · Department of Pathology, University of Washington, Harborview Medical Center, Seattle, Washington 98104, USA. · NeuroRx. · Pubmed #16815217 No free full text.

Abstract: 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.

Montine TJ, Quinn JF, Montine KS, Kaye JA, Breitner JC. · Department of Pathology, University of Washington, Seattle, WA 98104, USA. · J Alzheimers Dis. · Pubmed #16556967 No free full text.

Abstract: Dementia from Alzheimer's disease (AD) represents a significant and growing public health burden and presents a clear therapeutic imperative. Key to success in this undertaking will be biomarkers for the objective assessment of disease progression and response to therapeutics. Oxidative damage is one facet of AD pathogenesis for which there are experimentally validated quantitative in vivo biomarkers, the F2-isoprostanes (IsoPs). While plasma- or urine-based assays are desirable, consistent and reproducible cross-sectional data for increased F2-IsoPs in AD and mild cognitive impairment have been obtained only for CSF. In addition, measurement of CSF F2-IsoPs can increase the accuracy of laboratory-based classification of geriatric dementias, and have been used to assess objectively the response to anti-oxidant interventions in AD.

Shie FS, Montine KS, Breyer RM, Montine TJ. · Department of Pathology, University of Washington, Seattle 98104, USA. · Brain Pathol. · Pubmed #15912885 No free full text.

Abstract: Epidemiologic and animal model data support a role for the prostaglandin pathway in AD pathogenesis. However, unexpected toxicity from protracted use of some nonsteroidal anti-inflammatory drugs (NSAIDs) compels investigation of therapeutic targets in this pathway other than COX inhibitors. Previously, we have shown that mice lacking one specific receptor for PGE2, EP2 (EP2-/-), are protected from the indirect neurotoxic effects of cerebral innate immune response mediated by CD14-dependent activation. Here we review data showing that EP2-/- microglia have a highly desirable combination of features: ablated indirect neurotoxicity following exposure to Abeta(1-42) coupled with enhanced phagocytosis of Abeta peptides, both synthetic and those deposited in human brain. These data point to microglial EP2 as a more focused target within the PG pathway for therapy in AD.

Montine TJ, Morrow JD. · Department of Pathology, University of Washington, Box 359791, Seattle, WA 98104, USA. · Am J Pathol. · Pubmed #15855630 links to  free full text

Abstract: Alzheimer's disease (AD) is the most common dementing illness of the elderly and is a mounting public health problem. Pharmacoepidemiological data, analytical data from human tissue and body fluids, and mechanistic data mostly from murine models all have implicated oxidation products of two fatty acids, arachidonic acid (AA) and docosahexaenoic acid (DHA), in the pathogenesis of neurodegeneration. Here we review the biochemistry of AA and DHA oxidation, both enzyme-catalyzed and free radical mediated, and summarize those studies that have investigated these oxidation products as effectors of neurodegeneration and biomarkers of AD. Given the evolving appreciation for toxicity associated with current pharmaceuticals used to block AA and DHA oxidation, we close by speculating on likely areas of future research directed at suppressing this facet of neurodegeneration. If successful, these interventions are unlikely to cure AD, but may check its explosive growth and hopefully reduce its incidence and prevalence in the elderly.

Montine TJ, Montine KS, McMahan W, Markesbery WR, Quinn JF, Morrow JD. · Department of Pathology, University of Washington, Seattle, WA 98104, USA. · Antioxid Redox Signal. · Pubmed #15650414 No free full text.

Abstract: Increased free radical-mediated injury to brain is proposed to be an integral component of several neurodegenerative diseases, including Alzheimer's disease (AD). Lipid peroxidation is a major outcome of free radical- mediated injury to brain, where it directly damages membranes and generates a number of oxidized products. F2-Isoprostanes (F2-IsoPs), one group of lipid peroxidation products derived from arachidonic acid, are especially useful as in vivo biomarkers of lipid peroxidation. F2-IsoP concentration is selectively increased in diseased regions of brain from patients who died from advanced AD, where pathologic changes include amyloid beta (Abeta) amyloidogenesis, neurofibrillary tangle formation, and extensive neuron death. Interestingly, cerebral F2-IsoPs are not reproducibly elevated in aged mouse models of cerebral Abeta amyloidogenesis only. There is broad agreement that increased cerebrospinal fluid (CSF) levels of F2-IsoPs also are present in patients with early AD. Demonstrated applications of quantifying CSF F2-IsoPs have improved laboratory diagnostic accuracy of AD and objective assessment of antioxidant therapeutics. In contrast, quantification of F2-IsoPs in plasma and urine of AD patients has produced conflicting data. These results indicate that brain lipid peroxidation is a potential therapeutic target early in the course of AD, and that CSF F2-IsoPs may aid in the assessment of antioxidant experimental therapeutics and laboratory diagnosis of AD.

Montine KS, Quinn JF, Zhang J, Fessel JP, Roberts LJ, Morrow JD, Montine TJ. · Department of Pathology, University of Washington, Harborview Medical Center, Box 359791, 325 9th Ave., Seattle, WA 98104, USA. · Chem Phys Lipids. · Pubmed #15037157 No free full text.

Abstract: Lipid peroxidation is a major outcome of free radical-mediated injury to brain, where it directly damages membranes and generates a number of oxidized products. Some of the chemically and metabolically stable oxidation products are useful in vivo biomarkers of lipid peroxidation. These include the isoprostanes (IsoPs) and isofurans (IsoFs), derived from arachidonic acid (AA), and neuroprostanes (NeuroPs), derived from docosahexaenoic acid (DHA). We have shown increased levels of IsoPs, NeuroPs, and IsoFs in diseased regions of brain from patients who died from advanced Alzheimer's disease (AD) or Parkinson's disease (PD). Increased cerebrospinal fluid (CSF) levels of IsoPs are present in patients with AD or Huntington's disease (HD) early in the course of their illness, and CSF IsoPs may improve the laboratory diagnostic accuracy for AD. In contrast, quantification of IsoPs in plasma and urine of AD patients has yielded inconsistent results. These results indicate that brain lipid peroxidation is a potential therapeutic target early in the course of AD and HD, that CSF IsoPs may aid in the assessment of anti-oxidant experimental therapeutics and laboratory diagnosis of AD.

Bassett CN, Montine TJ. · University of Montevallo, Department of Biology, Chemistry, and Mathematics, AL 35115, USA. · J Nutr Health Aging. · Pubmed #12679837 No free full text.

Abstract: Alzheimer's Disease (AD) is a clinical-pathological entity that probably derives from different causes. Mounting evidence strongly implicates regionally increased oxidative damage to brain beyond what occurs with aging as one of the processes that may contribute to AD progression. While several different classes of molecules may be affected, lipid peroxidation is thought to be a prominent and especially deleterious form of oxidative damage in brain due to this organ's relative enrichment in polyunsaturated fatty acids. Our laboratory recently has demonstrated that lipoproteins in AD brain extracellular fluid are more vulnerable to oxidation than lipoproteins in control brain extracellular fluid. Apolipoprotein E (apoE) is the principal apolipoprotein in the central nervous system (CNS), and it serves as the major apolipoprotein that is capable of lipid transport and regulation of lipid metabolism through known receptor-mediated processes. Moreover, inheritance of the APOE4 allele represents the strongest genetic risk factor for sporadic AD. Evidence suggests that apoE isoforms may specifically influence the cellular distribution of lipid peroxidation products in brain and may therefore contribute to the stratification of risk for AD associated with APOE. Here, we review possible mechanisms whereby lipoprotein trafficking and lipid peroxidation converge to contribute to neurodegeneration in AD brain.

Picklo MJ, Montine TJ, Amarnath V, Neely MD. · Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Science, Grand Forks 58203, USA. · Toxicol Appl Pharmacol. · Pubmed #12460747 No free full text.

Abstract: A large amount of data has implicated reactive carbonyls as neurotoxic mediators of oxidative damage in the progression of Alzheimer's disease (AD) and other neurodegenerative diseases. The oxidation of polyunsaturated fatty acids, reducing sugars, and amino acids leads to the formation of carbonyls and carbonyl adduction products such as 4-hydroxy-2-nonenal (HNE), advanced glycation end products (AGEs), and protein-bound carbonyls. Levels of these products are elevated in AD. In this review, we examine the role that carbonyls may play in the development of this disease. We focus upon the chemistry of these molecules and the evidence for their involvement in AD. The biological effects of these carbonyl species in model systems and their relationship to AD are discussed. Lastly, we examine the potential mechanisms that the brain utilizes to detoxify carbonyl species and possible therapeutic interventions based on carbonyl detoxification.

Neely MD, Montine TJ. · Vanderbilt University Medical School, Department of Pathology, Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2561, USA. · J Nutr Health Aging. · Pubmed #12459889 No free full text.

Abstract: Alterations in lipid homeostasis have been suggested to play a role in the pathogenesis of Alzheimer's disease (AD). This hypothesis is supported by the observed changes in lipid content and composition of AD brains when compared to age-matched control brains. The association between the e4 allele of the apolipoprotein E gene and increased risk of AD implicates lipoproteins in the pathogenesis. Lipoproteins are macromolecular particles responsible for lipid trafficking and metabolism. CNS lipoproteins are different from their plasma counter parts. We review the current understanding of the structure and functions of CNS lipoproteins. In addition to mediating lipid trafficking and metabolism, there is increasing evidence that apoE-containing lipoproteins are also involved in dendritic remodeling and synaptogensis and maintenance of the synapto-dendritic complexity during aging. Interestingly, these functions have been shown to be apoE-isoform specific with apoE4 lacking the activities of apoE3 and apoE2. In addition to the association between apoE4 and an increased risk of AD, oxidative stress is believed to play a role in the pathogenesis of this disease. Indeed evidence of lipid peroxidation in cerebral spinal fluid (CSF) lipoproteins from AD patients has been observed. Oxidation of lipoproteins not only eliminates their supportive roles in neurite outgrowth and synaptogenesis, but actually transforms them into neurotoxic agents. The elucidation of the pathways and mechanisms by which apoE-isoform and oxidation affect lipoprotein function in the CNS remains a challenge for scientist in the field of neurodegenerative disease.

Montine TJ, Neely MD, Quinn JF, Beal MF, Markesbery WR, Roberts LJ, Morrow JD. · Department of Pharmacology, Pathology, and Medicine and the Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, USA. · Free Radic Biol Med. · Pubmed #12208348 No free full text.

Abstract: Lipid peroxidation is one of the major outcomes of free radical-mediated injury that directly damages membranes and generates a number of secondary products, both from fission and endocyclization of oxygenated fatty acids that possess neurotoxic activity. Numerous studies have demonstrated increased lipid peroxidation in brain of patients with Alzheimer's disease (AD) compared with age-matched controls. These data include quantification of fission and endocyclized products such as 4-hydroxy-2-nonenal, acrolein, isoprostanes, and neuroprostanes. Immunohistochemical and biochemical studies have localized the majority of lipid peroxidation products to neurons. A few studies have consistently demonstrated increased cerebrospinal fluid (CSF) levels of isoprostanes in AD patients early in the course of their dementia, and one study has suggested that CSF isoprostanes may improve the laboratory diagnostic accuracy for AD. Similar analyses of control individuals over a wide range of ages indicate that brain lipid peroxidation is not a significant feature of usual aging. Quantification of isoprostanes in plasma and urine of AD patients has yielded inconsistent results. These results indicate that brain lipid peroxidation is a potential therapeutic target in probable AD patients, and that CSF isoprostanes may aid in the assessment of antioxidant experimental therapeutics and the laboratory diagnosis of AD.

Bassett CN, Montine KS, Neely MD, Swift LL, Montine TJ. · Departments of Pathology and Pharmacology, and Center for Molecular Neurosciences at Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. · Microsc Res Tech. · Pubmed #10936881 No free full text.

Abstract: Interest in cerebrospinal fluid (CSF) lipoproteins has been stimulated by the association of certain alleles of the human apolipoprotein E gene (APOE) with an increased risk of Alzheimer's disease (AD), and because apolipoprotein E (apoE) is one of the major apolipoproteins in CSF. CSF lipoproteins (d < 1.210 g/ml fraction) are distinct from their plasma counterparts, and in AD patients CSF may contain novel particles. The protein concentration of CSF lipoproteins is reduced in AD patients. Moreover, the molecular distribution of apoE- and apoAII-containing apolipoproteins in CSF is dictated by APOE. The lipid composition suggests that CSF lipoproteins from AD patients may have undergone increased free radical-mediated damage; experimental data support the possibility that this may occur both before and after lipoprotein assembly. Finally, human CSF lipoproteins oxidized ex vivo are neurotoxic to neuronal cells in culture and disrupt microtubule structure, an activity not observed with oxidized bovine CSF lipoproteins. CSF lipoproteins may represent a means whereby apoE influences the outcome of free radical-mediated damage to brain.

Sonnen JA, Larson EB, Gray SL, Wilson A, Kohama SG, Crane PK, Breitner JC, Montine TJ. · Department of Pathology, University of Washington, Seattle, USA. · Ann Neurol. · Pubmed #19259965 No free full text.

Abstract: Evidence supports a pathogenic role for free radical injury to brain in Alzheimer's disease; however, clinical trial results are only mildly encouraging. Examining brains from The Adult Changes in Thought study offers a unique perspective. Selectively increased free radical damage to cerebral cortex was associated with Alzheimer's disease, microvascular brain injury, and current smoking, but not with antioxidant supplement usage. Our results support suppression of free radical injury to brain as a therapeutic target for Alzheimer's disease and microvascular brain injury; however, future clinical trials should consider other antioxidants or doses than those identified in our study.

Sonnen JA, Larson EB, Brickell K, Crane PK, Woltjer R, Montine TJ, Craft S. · Department of Pathology, University of Washington, Seattle, USA. · Arch Neurol. · Pubmed #19139294 No free full text.

Abstract: BACKGROUND: Diabetes mellitus (DM) increases the risk of dementia in the elderly. However, its underlying mechanisms, its connection with Alzheimer disease and vascular cognitive impairment, and effects of therapy remain unclear. OBJECTIVE: To test the hypothesis that DM promotes specific neuropathologic processes that contribute to dementia and that these processes may be suppressed by antidiabetic therapy. DESIGN: A comprehensive neuropathologic assessment of all cases from a community-based study of incident dementia (Adult Changes in Thought Study) that underwent autopsies (n = 259) and had information on DM status (n = 196). Biochemical analysis was conducted on a subset of these cases with rapidly frozen brain tissue (n = 57). PARTICIPANTS: Autopsy cases were divided into 4 groups: no DM/no dementia (DM-/dementia-), DM/no dementia (DM+/dementia-), no DM/dementia (DM-/dementia+), and DM/dementia (DM+/dementia+). Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnosis of dementia was assigned through a consensus of experts following biennial cognitive and physical evaluations. Diabetes was diagnosed based on information obtained from participants' extensive medical records. RESULTS: In cases without dementia (n = 125), neuropathologic and biochemical end points did not differ significantly by DM status. However, we observed 2 patterns of injury in patients with dementia (n = 71) by their DM status. Individuals without DM but with dementia (DM-/dementia+) had a greater amyloid-beta peptide load and increased levels of F(2)-isoprostanes in the cerebral cortex, while DM+/dementia+ patients had more microvascular infarcts and an increased cortical IL-6 (interleukin 6) concentration. The number of microvascular infarcts was greater in deep cerebral structures in patients with dementia whose diabetes was treated, whereas amyloid plaque load tended to be greater for untreated diabetic patients with dementia. CONCLUSIONS: These novel characterizations of 2 different patterns of cerebral injury in patients with dementia depending on DM status may have etiologic and therapeutic implications. Published online January 12, 2009 (doi:10.1001/archneurol.2008.579).

Duerson K, Woltjer RL, Mookherjee P, Leverenz JB, Montine TJ, Bird TD, Pow DV, Rauen T, Cook DG. · Geriatric Research Education and Clinical Center, VA Medical Center, 1660 S. Columbian Way, Seattle, WA 98108, USA. · Brain Pathol. · Pubmed #18624794 No free full text.

Abstract: Disturbed glutamate homeostasis may contribute to the pathological processes involved in Alzheimer's disease (AD). Once glutamate is released from synapses or from other intracellular sources, it is rapidly cleared by glutamate transporters. EAAC1 (also called EAAT3 or SLC1A1) is the primary glutamate transporter in forebrain neurons. In addition to transporting glutamate, EAAC1 plays other roles in regulating GABA synthesis, reducing oxidative stress in neurons, and is important in supporting neuron viability. Currently, little is known about EAAC1 in AD. To address whether EAAC1 is disturbed in AD, immunohistochemistry was performed on tissue from hippocampus and frontal cortex of AD and normal control subjects matched for age and gender. While EAAC1 immunostaining in cortex appeared comparable to controls, in the hippocampus, EAAC1 aberrantly accumulated in the cell bodies and proximal neuritic processes of CA2-CA3 pyramidal neurons in AD patients. Biochemical analyses showed that Triton X-100-insoluble EAAC1 was significantly increased in the hippocampus of AD patients compared to both controls and Parkinson's disease patients. These findings suggest that aberrant glutamate transporter expression is associated with AD-related neuropathology and that intracellular accumulation of detergent-insoluble EAAC1 is a feature of the complex biochemical lesions in AD that include altered protein solubility.

Musiek ES, Brooks JD, Joo M, Brunoldi E, Porta A, Zanoni G, Vidari G, Blackwell TS, Montine TJ, Milne GL, McLaughlin B, Morrow JD. · Division of Clinical Pharmacology, and Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. · J Biol Chem. · Pubmed #18490445 links to  free full text

Abstract: The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) possesses potent anti-inflammatory properties and has shown therapeutic benefit in numerous inflammatory diseases. However, the molecular mechanisms of these anti-inflammatory properties are poorly understood. DHA is highly susceptible to peroxidation, which yields an array of potentially bioactive lipid species. One class of compounds are cyclopentenone neuroprostanes (A(4)/J(4)-NPs), which are highly reactive and similar in structure to anti-inflammatory cyclopentenone prostaglandins. Here we show that a synthetic A(4)/J(4)-NP, 14-A(4)-NP (A(4)-NP), potently suppresses lipopolysaccharideinduced expression of inducible nitric-oxide synthase and cyclooxygenase-2 in macrophages. Furthermore, A(4)-NP blocks lipopolysaccharide-induced NF-kappaB activation via inhibition of Ikappa kinase-mediated phosphorylation of IkappaBalpha. Mutation on Ikappa kinase beta cysteine 179 markedly diminishes the effect of A(4)-NP, suggesting that A(4)-NP acts via thiol modification at this residue. Accordingly, the effects of A(4)-NP are independent of peroxisome proliferator-activated receptor-gamma and are dependent on an intact reactive cyclopentenone ring. Interestingly, free radical-mediated oxidation of DHA greatly enhances its anti-inflammatory potency, an effect that closely parallels the formation of A(4)/J(4)-NPs. Furthermore, chemical reduction or conjugation to glutathione, both of which eliminate the bioactivity of A(4)-NP, also abrogate the anti-inflammatory effects of oxidized DHA. Thus, we have demonstrated that A(4)/J(4)-NPs, formed via the oxidation of DHA, are potent inhibitors of NF-kappaB signaling and may contribute to the anti-inflammatory actions of DHA. These findings have implications for understanding the anti-inflammatory properties of omega-3 fatty acids, and elucidate novel interactions between lipid peroxidation products and inflammation.

Zhang J, Sokal I, Peskind ER, Quinn JF, Jankovic J, Kenney C, Chung KA, Millard SP, Nutt JG, Montine TJ. · Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104, USA. · Am J Clin Pathol. · Pubmed #18343778 links to  free full text

Abstract: The therapeutic imperative for Alzheimer disease (AD) and Parkinson disease (PD) calls for discovery and validation of biomarkers. Increased cerebrospinal fluid (CSF) tau and decreased amyloid (A) beta42 have been validated as biomarkers of AD. In contrast, there is no validated CSF biomarker for PD. We validated our proteomics-discovered multianalyte profile (MAP) in CSF from 95 control subjects, 48 patients with probable AD, and 40 patients with probable PD. An optimal 8-member MAP agreed with expert diagnosis for 90 control subjects (95%), 36 patients with probable AD (75%), and 38 patients with probable PD (95%). This MAP consisted of the following (in decreasing order of contribution): tau, brain-derived neurotrophic factor, interleukin 8, Abeta42, beta2-microglobulin, vitamin D binding protein, apolipoprotein (apo) AII, and apoE. This first large-scale validation of a proteomic-discovered MAP suggests a panel of 8 CSF proteins that are highly effective at identifying PD and moderately effective at identifying AD.

Li G, Larson EB, Sonnen JA, Shofer JB, Petrie EC, Schantz A, Peskind ER, Raskind MA, Breitner JC, Montine TJ. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. · Neurology. · Pubmed #17724290 No free full text.

Abstract: BACKGROUND: Treatment with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors ("statins") has been associated in some epidemiologic studies with reduced risk of Alzheimer disease (AD). However, direct evidence of statin effects on neuropathologic markers of AD is lacking. We investigated whether antecedent statin exposure is associated with neuritic plaque (NP) or neurofibrillary tangle (NFT) burden in a population-based sample of human subjects. METHODS: Brain autopsies were performed on 110 subjects, ages 65 to 79 years, who were cognitively normal at enrollment into the Adult Changes in Thought Study. Neuropathologic findings were compared between statin users with > or =3 prescriptions of > or =15 pills of simvastatin, pravastatin, lovastatin, or atorvastatin vs nonusers, based on pharmacy dispensing records. RESULTS: After controlling for age at death, gender, cognitive function at study entry, brain weight, and presence of cerebral microvascular lesions, the odds ratio (OR) for each unit increase in Braak NFT stage in statin users vs nonusers was 0.44 (95% CI: 0.20 to 0.95). The OR for each unit increase in Consortium to Establish a Registry for Alzheimer's Disease (CERAD) staging of NPs did not deviate significantly from unity (OR 0.69; 95% CI: 0.32 to 1.52). However, the risk for typical AD pathology (Braak stage > or = IV and CERAD rating > or = moderate) was reduced in statin users (OR 0.20; 95% CI: 0.05 to 0.86). CONCLUSIONS: These findings demonstrate an association between antecedent statin use and neurofibrillary tangle burden at autopsy. Additional study is needed to examine whether statin use may be causally related to decreased development of Alzheimer disease-related neuropathologic changes.

Li G, Sokal I, Quinn JF, Leverenz JB, Brodey M, Schellenberg GD, Kaye JA, Raskind MA, Zhang J, Peskind ER, Montine TJ. · Mental Illness Research, Education, and Clinical Center and Department of Psychiatry, VA Puget Sound Health Care System, University of Washington, Seattle, WA, USA. · Neurology. · Pubmed #17698783 No free full text.

Abstract: BACKGROUND: Processes of Alzheimer disease (AD) likely begin years prior to the onset of cognitive impairment (latent AD), progress though a prodromal phase of mild cognitive impairment (MCI), and culminate in dementia. While many studies have evaluated CSF tau and Abeta(42) as biomarkers of the dementia or prodromal stages of AD, we are unaware of any study to evaluate these potential CSF biomarkers of latent AD. METHODS: We determined the ratio of CSF tau/Abeta(42) (T/Abeta) using Luminex reagents in 129 control individuals that spanned from 21 to 100 years of age; for comparison we included patients with MCI (n = 12), probable AD (n = 21), or other neurodegenerative diseases (n = 12). RESULTS: We identified 16% of the control group with abnormally elevated CSF T/Abeta; all were 53 years or older. Using age-matched controls with normal CSF T/Abeta we showed that the high CSF T/Abeta subgroup of controls had significantly increased frequency of the epsilon4 allele of the apolipoprotein E gene and significantly increased risk of conversion to MCI during follow-up of up to 42 months suggesting that they had latent AD at the time of lumbar puncture. CONCLUSIONS: These generally applicable methods establish cutoff values to identify control individuals at increased risk of conversion to mild cognitive impairment which may be useful to people weighing the risk-benefit ratio of new preventive therapeutics and to researchers striving to enrich clinical trial populations with people with latent Alzheimer disease.

Riekse RG, Li G, Petrie EC, Leverenz JB, Vavrek D, Vuletic S, Albers JJ, Montine TJ, Lee VM, Lee M, Seubert P, Galasko D, Schellenberg GD, Hazzard WR, Peskind ER. · Department of Medicine, Division of Geriatric Medicine, University of Washington School of Medicine, and VA Puget Sound Health Care System, Seattle, WA 98108, USA. · J Alzheimers Dis. · Pubmed #17183151 No free full text.

Abstract: BACKGROUND: Treatment with HMG-CoA reductase inhibitors ("statins") has been variably associated with a reduced risk of Alzheimer's disease (AD) in epidemiologic studies and reduced amyloid-beta (Abeta) deposition in animal models of AD. Putative neuroprotective effects of statins may vary in relation to their ability to penetrate into the central nervous system (CNS). METHODS: We measured levels of cerebrospinal fluid (CSF) AD biomarkers following 14 weeks of treatment with simvastatin (a CNS permeant statin; n=10) at 40 mg/day or pravastatin (a CNS impermeant statin; n=13) at 80 mg/day in hypercholesterolemic subjects without dementia. RESULTS: Simvastatin, but not pravastatin, reduced CSF levels of phospho-tau-181 (p-tau181) in all subjects. There were no differences in CSF levels of total tau, Abeta42, Abeta40, soluble amyloid beta protein precursor (sAbetaPP) alpha or beta, or F2-isoprostanes. CONCLUSIONS: Statins may modulate the phosphorylation of tau in humans and this effect may depend on the CNS availability of the statin. These results suggest another mechanism by which statins may act to reduce the risk of AD.

Dodson SE, Gearing M, Lippa CF, Montine TJ, Levey AI, Lah JJ. · Center for Neurodegenerative Disease, Department of Neurology, Emory University Atlanta, Georgia 30322, USA. · J Neuropathol Exp Neurol. · Pubmed #16957580 links to  free full text

Abstract: LR11 is an ApoE receptor that is enriched in the brain. We have shown that LR11 is markedly downregulated in patients with sporadic Alzheimer disease (AD). This finding led us to explore whether reduced LR11 expression reflects a primary mechanism of disease or merely a secondary consequence of other AD-associated changes. Therefore, LR11 expression was assessed in a transgenic mouse model of AD and familial AD (FAD) brains. Immunohistochemistry and immunoblotting of LR11 in PS1/APP transgenic and wild-type mice indicated that LR11 levels are not affected by genotype or accumulation of amyloid pathology. LR11 expression was also evaluated based on immunoblotting and LR11 immunostaining intensity in human frontal cortex in controls, sporadic AD, and FAD, including cases with presenilin-1 (PS1) and presenilin-2 (PS2) mutations. Although LR11 was reduced in sporadic AD, there was no difference in protein level or staining intensity between control and FAD cases. The finding that LR11 expression is unaffected in both a mouse model of AD and autosomal-dominant forms of AD suggests that LR11 is not regulated by amyloid accumulation or other AD neuropathologic changes. We hypothesize that LR11 loss may be specific to sporadic AD and influence amyloid pathology through mechanisms independent of substrate-enzyme interactions regulated by FAD mutations.