AGING BRAIN AGING INFLAMMATORY, ARACHIDONIC ACID CASCADE, AND SYNAPTIC CHANGES. Aging is a risk factor for Alzheimer's disease (AD) and is associated with cognitive decline. Recent studies suggest epigenetic influences on gene expression in AD, as DNA methylation levels influence protein and mRNA expression in postmortem AD brain. We hypothesized that some of these changes occur with normal aging. We measured markers of the arachidonic acid (AA) cascade, neuroinflammation, pro- and anti-apoptosis factors, and gene specific epigenetic modifications in postmortem frontal cortex from nine middle-aged 41 +/- 1 (SEM) years and 10 aged subjects (70 +/- 3 years). Aged compared with middle-aged brain showed elevated levels of neuroinflammatory and AA cascade markers, altered pro and anti-apoptosis factors and loss of synaptophysin. Some of these changes correlated with promoter hypermethylation of brain derived neurotrophic factor (BDNF), cyclic AMP responsive element binding protein (CREB), and synaptophysin and hypomethylation of BCL-2 associated X protein (BAX). These molecular alterations in aging indicate how aging is a risk factor for AD. (1) SCHIZOPHRENIA INCREASED NEUROINFLAMMATORY AND ARACHIDONIC ACID CASCADE MARKERS, AND REDUCED SYNAPTIC PROTEINS, IN SCHIZOPHRENIA. Schizophrenia (SZ) is a progressive, neuropsychiatric disorder associated with cognitive impairment. A number of brain alterations have been linked to cognitive impairment, including neuroinflammation, excitotoxicity, increased arachidonic acid (AA) signaling and reduced synaptic protein. On this basis, we tested the hypothesis that SZ pathology is associated with these pathological brain changes. We examined postmortem frontal cortex from 10 SZ patients and 10 controls. Mean protein and mRNA levels of interleukin-1beta, tumor necrosis factor-alpha, glial acidic fibrillary protein (GFAP), a microglial marker CD11b, and nuclear factor kappa B subunits were significantly increased in SZ brain. Protein and mRNA levels of cytosolic and secretory phospholipase A2 and cyclooxygenase also were significantly elevated. N-methyl-d-aspartate receptor subunits 1 and 2B, inducible nitric oxide synthase and c-Fos were not significantly different. In addition, reduced protein and mRNA levels of brain-derived neurotrophic factor, synaptophysin and drebrin were found in SZ compared with control cortex. These changes likely contribute to disease progression and cognitive defects in SZ patients. Drugs that dampen them might be considered for new therapies. (2) ALTERED FATTY ACID CONCENTRATIONS IN PREFRONTAL CORTEX IN SCHIZOPHRENIA. Disturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in patients with schizophrenia (SCZ), often as an incomplete lipid profile or a percent of total lipid concentration. We quantified absolute concentrations (nmol/g wet weight) of several lipid classes and their constituent fatty acids in postmortem prefrontal cortex of SCZ patients (n = 10) and age-matched controls (n = 10). Mean brain total lipid, phospholipid, individual phospholipids, plasmalogen, triglyceride and cholesteryl ester concentrations did not differ significantly between groups. Compared to controls, SCZ brains showed significant increases in several monounsaturated and polyunsaturated fatty acid concentrations in cholesteryl ester. Significant increases or decreases occurred in palmitoleic, linoleic, gamma-linolenic and n-3 docosapentaenoic acid concentrations in total lipids, triglycerides or phospholipids. Changes in fractional concentrations did not consistently reflect absolute concentration changes. Disturbed prefrontal cortex fatty acid concentrations, particularly within cholesteryl esters, are a pathological aspect of SCZ.(3). HUNTINGTON DISEASE CEREBROSPINAL FLUID MYOINOSITOL IN HUNTINGTON DISEASE. Huntington disease (HD) is a devastating hereditary disorder of the brain. It is inherited as an autosomal, dominant disorder associated with increases in the length of the CAG triplet repeat in the Huntington disease gene on chromosome 4. Thus there is a 50% risk that each child of a person with the CAG expansion for HD will inherit the disease. The cerebrospinal fluid (CSF) is an invaluable tool in the diagnosis of a variety of diseases. Successful identification of HD-associated protein biomarkers in CSF would have multiple applications in understanding the natural history of HD, in performing clinical drug trials and in identifying pathogenic processes in the brain and the periphery. Validated biomarkers could provide more specificity and sensitivity for early efficacy, thereby reducing the cost and time for drug development. We have published an analytical method to measure CSF polyols, and using it have shown elevated myoinositol in CSF from Down syndrome but not Alzheimer disease patients (Shetty et al. J Clin Invest, 99, 542, 1995). In this study, we are testing the hypothesis that increased levels of CSF myo-inositol will be found in patients with HD compared with controls, and could be used with other biomarkers to initiate treatments and evaluate their efficacy in HD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000428-06
Application #
8736563
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$338,770
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Taha, Ameer Y; Cheon, Yewon; Ma, Kaizong et al. (2013) Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients. J Psychiatr Res 47:636-43
Rao, Jagadeesh Sridhara; Kim, Hyung-Wook; Harry, Gaylia Jean et al. (2013) Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr Res 147:24-31
Rao, J S; Harry, G J; Rapoport, S I et al. (2010) Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry 15:384-92
Stolk, Pieter; Souverein, Patrick C; Wilting, Ingeborg et al. (2010) Is aspirin useful in patients on lithium? A pharmacoepidemiological study related to bipolar disorder. Prostaglandins Leukot Essent Fatty Acids 82:9-14
Rao, Jagadeesh S; Rapoport, Stanley I; Kim, Hyung-Wook (2009) Decreased GRK3 but not GRK2 expression in frontal cortex from bipolar disorder patients. Int J Neuropsychopharmacol 12:851-60