Elevated plasma neopterin levels in Alzheimer disease.

We assessed plasma neopterin level as a marker of inflammation in Alzheimer disease (AD). Plasma neopterin levels were higher in 51 patients with AD (9.3 +/- 5.

Altered expression of a-type but not b-type synapsin isoform in the brain of patients at high risk for Alzheimer's disease assessed by DNA microarray technique.

Using a cDNA microarray representing 6794 distinct human genes, we identified candidate genes whose expression is altered in cerebral cortex of cases of early Alzheimer's disease (AD); among these was the synaptic vesicle protein synapsin II, which plays an important role in neurotransmitter release. While other candidate genes are presently under investigation in our lab, in this study we discuss the regulation of synapsin gene expression during the transition from normal cognitive function to early AD. We found a selective decrease in the expression of the synapsin splice variants I-III of the a-type isoform in the entorhinal (EC, BM36) but not visual cortex (VC, BM17) of cases characterized by the earliest clinically detectable stage of AD.

Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia.

Background: Inflammatory cytokines have been linked to Alzheimer disease (AD) neurodegeneration, but little is known about the temporal control of their expression in relationship to clinical measurements of AD dementia progression.

Design And Main Outcome Measures: We measured inflammatory cytokine messenger RNA (mRNA) expression in postmortem brain specimens of elderly subjects at different clinical stages of dementia and neuropathological dysfunction.

Setting And Patients: Postmortem study of nursing home patients.

Inflammation and Alzheimer's disease.

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation.

The role of complement anaphylatoxin C5a in neurodegeneration: implications in Alzheimer's disease.

There is evidence that the complement system, a major component of inflammatory responses, may play an important role in neurodegenerative conditions such as Alzheimer's disease (AD). Work from our lab demonstrated that mice genetically deficient in the complement component C5 are more susceptible to hippocampal excitotoxic lesions (Pasinetti et al., 1996) and that the C5-derived ana;hylatoxin C5a may protect against excitotoxicity in vitro and in vivo (Osaka et al.

Protein kinase C anchoring deficit in postmortem brains of Alzheimer's disease patients.

Protein kinase C (PKC) has been implicated in the pathophysiology of Alzheimer's disease (AD). The levels of particular isoforms and the activation of PKC are reduced in postmortem brain cortex of AD subjects. Receptors for activated C kinase (RACK) are a family of proteins involved in anchoring activated PKCs to relevant subcellular compartments.

Potentiation of excitotoxicity in transgenic mice overexpressing neuronal cyclooxygenase-2.

In this study we describe the generation of a transgenic mouse model with neuronal overexpression of the human cyclooxygenase-2, h(COX)-2, to explore its role in excitotoxicity. We report that overexpression of neuronal hCOX-2 potentiates the intensity and lethality of kainic acid excitotoxicity in coincidence with potentiation of expression of the immediate early genes c-fos and zif-268. In vitro studies extended the in vivo findings and revealed that glutamate excitotoxicity is potentiated in primary cortico-hippocampal neurons derived from hCOX-2 transgenic mice, possibly through potentiation of mitochondrial impairment.

Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease.

Cyclooxygenase-2 (COX-2), a key enzyme in prostanoid biosynthesis, may represent an important therapeutic target in Alzheimer's disease (AD). In the present study, we explored the regulation of COX-2 in the hippocampal formation in sporadic AD. Using semiquantitative immunocytochemical techniques, we found that in AD cases (vs.

Expression of C5a receptor in mouse brain: role in signal transduction and neurodegeneration.

In this study we explored the potential role of the complement derived anaphylatoxin C5a and the expression of its receptor in mouse brain. Using in situ hybridization, we found that C5a receptor messenger RNA is expressed in mouse brain. In response to intraventricular kainic acid injection, there was marked increase in the C5a receptor messenger RNA expression, particularly in hippocampal formation and cerebral cortex.

Complement-derived anaphylatoxin C5a protects against glutamate-mediated neurotoxicity.

Previous work from this laboratory indicates a role for the complement component C5 in neuroprotection against excitotoxicity. In the present study, we tested the hypothesis that the C5-derived anaphylatoxin C5a protects against kainic acid (KA)-induced neurodegeneration and investigated the mechanism of C5a neuronal activity in vitro. Brain intraventricular infusion of KA into adult mice caused neuronal morphological features of apoptosis in the pyramidal layer of the hippocampal formation as indicated by counts of neurons with pyknotic/condensed nuclei associated with cytoplasmic eosinophilia.

Glycoprotein 330/megalin (LRP-2) has low prevalence as mRNA and protein in brain microvessels and choroid plexus.

Prior studies indicated that glycoprotein 330 (gp330)/megalin mediates transcytosis of apolipoprotein J (apoJ) with Alzheimer's amyloide-peptide (Abeta) across the vascular membranes of the central nervous system (CNS). Here we show the presence of gp330/megalin mRNA and gp330-like immunoepitopes in brain capillaries and choroid plexus and their absence from brain parenchyma. By polymerase chain reaction (PCR) we estimated 1.

Glial gene expression during aging in rat striatum and in long-term responses to 6-OHDA lesions.

The male rat striatum was examined for age-related changes in mRNAs expressed in astrocytes and microglia in two rat genotypes that differ by 35% in mean and maximum life spans: F344 and the longer-lived F1 (BN x F344) hybrid. The findings extend the established age-related increases in GFAP (glial fibrillary acidic protein) to other glial mRNAs: two lipoprotein mRNAs that are predominantly expressed in striatal astrocytes, apoE (apolipoprotein E) and apoJ (apolipoprotein J, clusterin, CLI, or SGP-2), and two mRNAs expressed in striatal microglia, TGF-beta1 and complement C1qB. By Northern blot hybridization, both genotypes showed progressive increases of GFAP mRNA to > 2.

HLA-DR4 influences glial activity in Alzheimer's disease hippocampus.

The importance of inflammatory/immune mechanisms in Alzheimer's disease is supported by evidence that the human leukocyte antigen (HLA)-DR genotype influences risk of the disease, with a protective effect associated with the HLA-DR4 allele. We investigated the influence of the HLA-DR4 allele on glial activity, assessed by quantification of glial fibrillary acidic protein (GFAP), in hippocampal tissue from subjects with Alzheimer's disease. The mean GFAP level was significantly higher in Alzheimer's disease hippocampal specimens lacking the HLA-DR4 allele compared to specimens with similar neuropathological findings that were HLA-DR4 positive.

Cyclooxygenase and inflammation in Alzheimer's disease: experimental approaches and clinical interventions.

Many epidemiological studies suggest that use of non-steroidal anti-inflammatory drugs (NSAIDs) delay or slow the clinical expression of Alzheimer's disease (AD). While it has been demonstrated that neurodegeneration in AD is accompanied by specific inflammatory mechanisms, including activation of the complement cascade and the accumulation and activation of microglia, the mechanism by which NSAIDs might affect these or other pathophysiological processes relevant to AD has been unclear. New evidence that cyclooxygenase (COX) is involved in neurodegeneration along with the development of selective COX inhibitors has led to renewed interest in the therapeutic potential of NSAIDs in AD.

Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer's disease brain.

Many epidemiological studies suggest that use of nonsteroidal anti-inflammatory drugs delays or slows the clinical expression of Alzheimer's disease, but the mechanism by which these drugs might affect pathophysiological processes relevant to Alzheimer's disease has been unclear. Non-steroidal anti-inflammatory drugs are presumed to act by inhibiting cyclooxygenase, a key enzyme in the metabolism of membrane-derived arachidonic acid into prostaglandins. In recent years, two distinct isoforms of cyclooxygenase have been characterized, a constitutive form, cyclooxygenase-1, and a mitogen-inducible form, cyclooxygenase-2.

Induction of cyclooxygenase (COX)-2 but not COX-1 gene expression in apoptotic cell death.

In this study we assessed the regulation of cyclooxygenase (COX)-2 in models of apoptotic cell death in vivo and in vitro. By 6 h after hippocampal colchicine injection in rat, COX-2 (but not COX-1) mRNA expression was elevated. The induction of COX-2 mRNA expression preceded temporally and overlapped anatomically the cellular morphological features of apoptosis in the granule cell layer of the dentate gyrus.

[A case of congenital hepatic hemangioendothelioma treated with prednisone: the echographic changes and Doppler study].

Imaging investigations and other findings observed in a term infant with a multicentric hepatic hemangioendothelioma, admitted to the Intensive Care Unit at the age of 13 days because of non specified feeding difficulties and dyspnoea, are presented. Physical examination revealed cardiac bruit and congestive heart failure with marked hepatomegaly; in addition there were multiple small skin hemangiomas. Echocardiography was negative, abdominal sonography showed multiple round lesions of mixed echogenicity in the liver, large vascular channels, a right hepatic artery and hepatic veins enlarged, a caliber of the aorta below the level of the superior mesenteric artery reduced.

Glucocorticoids in Alzheimer's disease. The story so far.

The inflammatory hypothesis of Alzheimer's disease states that specific inflammatory mechanisms, including the cytokine-driven acute-phase response, complement activation and microglial activation, contribute to neurodegeneration. If the hypothesis is correct, anti-inflammatory treatment aimed at suppression of these mechanisms could slow the rate of disease progression. Towards this goal, a multicentre trial of prednisone in Alzheimer's disease is under way and pilot studies of other anti-inflammatory regimens are being conducted.

Complement and glutamate neurotoxicity. Genotypic influences of C5 in a mouse model of hippocampal neurodegeneration.

Using mice genetically deficient in the complement (C)-system component C5, this study explored a potential novel role of the C-system in Ca(2+)-mediated control of glutamate AMPA receptor functions. We found that Ca2+ preincubation of frozen brain tissue sections enhances AMPA binding capacity more dynamically in C5 deficient (C5-) than congenic C5 sufficient (C5+) mice. The Ca(2+)-mediated response was mostly localized to the CA3 and CA1 subdivisions of the pyramidal layers of the hippocampal formation.

Maturational regulation and regional induction of cyclooxygenase-2 in rat brain: implications for Alzheimer's disease.

We explored the constitutive expression, maturational regulation, and relation to kainic-acid-induced apoptosis of cyclooxygenase (COX)-2 mRNA in rat brain. In adult rats, COX-2 mRNA was expressed primarily in limbic structures. Constitutive COX-2 mRNA expression increased markedly between Postnatal Day 7 (P7) and P14, reaching adult levels by P21.

Inflammatory mechanisms in neurodegeneration and Alzheimer's disease: the role of the complement system.

This review discusses key findings indicating potential roles of the complement (C)-system in chronic inflammation in Alzheimer's disease (AD) brain. Although there is no means to cure or prevent the disease, recent studies suggest that antiinflammatory drugs may delay the onset of AD dementia. One target of these drugs may be the (C)-system, which is best known for its roles in inflammatory processes in peripheral tissues.

Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions.

Possible roles of the complement (C) system in the normal and injured brain were explored with inbred mice that carried a frameshift mutation in the C5 gene. A congenic pair was used: the C5-sufficient (C5+) B10.D2/nSnJ strain with the functional allele (Hc1) from the C57BL/10J donor strain was compared with the C5-deficient (C5-) B10.