Lipids in Human Brain Disease

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COORDINATION OF GENE EXPRESSION OF ARACHIDONIC AND DOCOSAHEXAENOIC ACID CASCADE ENZYMES DURING HUMAN BRAIN DEVELOPMENT AND AGING. The polyunsaturated arachidonic and docosahexaenoic acids (AA and DHA) participate in neuroplasticity and neurotransmission throughout life. Each is metabolized via enzymatic reactions within separate but interacting metabolic cascades. We showed that AA and DHA pathway genes are coordinately expressed and underlie cascade interactions during human brain development and aging. We used the publically available BrainCloud database for human non-pathological prefrontal cortex gene expression to quantify postnatal age changes in mRNA expression of 34 genes involved in AA and DHA metabolism. Expression patterns were split into Development (0 to 20 years) and Aging (21 to 78 years) intervals. Expression of genes for cytosolic phospholipases A2 (cPLA2), cyclooxygenases (COX)-1 and -2, and other AA cascade enzymes, correlated closely with age during Development, less so during Aging. Expression of DHA cascade enzymes was less inter-correlated, but often changed in the opposite direction to expression of AA cascade genes. Thus, coordinated age-related gene expression during the brain Development and Aging intervals likely underlies coupled changes in enzymes of the AA and DHA cascades and largely occur through distant transcriptional regulation. Healthy brain aging does not show upregulation of PLA2G4 or PTGS2 expression, which was found in Alzheimer's disease. (1) CORRELATED EXPRESSION CHANGES IN GENES INVOLVED IN PHOSPHOINOSITIDE SIGNALING PATHWAYS DURING HUMAN BRAIN DEVELOPMENT AND AGING. Phosphoinositides are important signaling molecules that participate in diverse cellular processes, including neurotransmission, autophagy, apoptosis, cell growth, and membrane trafficking. As in the prior report, we are studying 49 genes involved in phosphoinositide signaling using the BrainCloud database for the human prefrontal cortex. Heat maps showing correlations between each pair of genes showed groups of highly intercorrelated genes that were also functionally related in different ways during the Development and Aging periods. This work is in progress. COORDINATED GENE EXPRESSION OF NEUROINFLAMMATORY AND CELL SIGNALING MARKERS IN DORSOLATERAL PREFRONTAL CORTEX DURING HUMAN BRAIN DEVELOPMENT AND AGING. We showed that expression levels of inflammatory, synaptic, and neurotrophic genes in the human brain are coordinated over the lifespan and underlie changes in phenotypic networks or cascades, using a large-scale microarray dataset from human prefrontal cortex, BrainCloud, divided into Development (0 to 21 years, 87 brains) and Aging (22 to 78 years, 144 brains) intervals. Expression levels for 39 genes followed different trajectories over the lifespan, and were correlated differently in the two intervals. Many changes were intercorrelated within three similar groups or clusters of genes during both Development and Aging, despite different roles of the gene products in the two intervals. During Development, changes were related to reported neuronal loss, dendritic growth and pruning, and microglial events; TLR4, IL1R1, NFKB1, MOBP, PLA2G4A, and PTGS2 expression increased in the first years of life, while expression of synaptic genes GAP43 and DBN1 decreased, before reaching plateaus. During Aging, expression was upregulated for potentially pro-inflammatory genes such as NFkB1, TRAF6, TLR4, IL1R1, TSPO, and GFAP, but downregulated for neurotrophic and synaptic integrity genes such as BDNF, NGF, PDGFA, SYN, and DBN1. This work is being submitted for publication. AGING TRENDS OF BRAIN-DERIVED NEUROTROPHIC FACTOR IN THE GRAY AND WHITE MATTER OF SCHIZOPHRENIA PATIENTS. We hypothesized that BDNF plays a role in the abnormal brain aging reported in schizophrenia. We tested this hypothesis by measuring BDNF protein levels in postmortem gray matter of prefrontal cortex (PFC) and white matter of the genu of the corpus callosum from 20 schizophrenia patients and 20 matched controls across the adult lifespan, from 20-80 years. PFC gray matter BDNF protein levels declined significantly with age in both controls and patients, while BDNF in white matter did not decrease significantly with age in either group. PFC BDNF decreased linearly from 20 to 80 years of age in controls. In schizophrenia, the rate of decline was similarly linear in younger patients but a decline did not occur in older patients. Thus, PFC BDNF did not follow a normative linear decline in schizophrenia patients as they grow older, which may represent a floor effect due to earlier decline, or a survivor cohort of older patient donors who are less susceptible to a schizophrenia-related pathological aging process. Submitted for publication. CEREBROSPINAL FLUID MYOINOSITOL IN HUNTINGTON DISEASE. Huntington disease (HD) is a devastating hereditary disorder of the brain. Identification of HD-associated biomarkers in cerebrospinal fluid (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. We have published an analytical method to measure CSF polyols, and used it to show elevated myoinositol in CSF from Down syndrome but not Alzheimer disease patients (Shetty et al. J Clin Invest, 99, 542, 1995). In this collaborative study with Dr. Blair Levitt at Univ. British Columbia, we are testing the hypothesis that increased levels of CSF myo-inositol will be found in HD patients compared with controls. ANAKINRA, A RECOMBINANT HUMAN IL-1 RECEPTOR ANTAGONIST, FOR TREATING NEUROINFLAMMATION IN HIV-1 INFECTION. While the advent of antiretroviral therapy has led to a decreased incidence of the most severe form of HIV associated cognitive dysfunction (HAND), HAND prevalence is estimated at 20%-69% in different population studies of virally-controlled patients. There is evidence that HIV-1 infection of the brain stimulates the innate and adaptive immune systems, and causes neuroinflammation involving excess secretion of cytokines including interleukin-1β (IL-1β) by activated resident microglia, thereby stimulating IL-1 receptors on reactive astrocytes, and initiating a neuropathological cascade that may contribute to HAND and involve arachidonic acid. Stimulation by the IL-1 family of cytokines of the IL-1 receptor induces expression of IL-1 target genes including IL-6, initiating a neuroinflammatory cascade. In a collaboration involving NINDS and NIAID, with Drs. Avindra Nath and Chuen-Yen Lau, we are preparing a clinical protocol to test if administering Anakinra, a recombinant non-glycosylated human interleukin-1 receptor antagonist, will interrupt the neuroinflammatory cascade in HIV-1 subjects on ART and mitigate HAND.