Showing papers by "Patrick L. McGeer published in 2001"

Generation of C-reactive protein and complement components in atherosclerotic plaques.

Abstract: C-reactive protein (CRP) and complement are hypothesized to be major mediators of inflammation in atherosclerotic plaques. We used the reverse transcriptase-polymerase chain reaction technique to detect the mRNAs for CRP and the classical complement components C1 to C9 in both normal arterial and plaque tissue, establishing that they can be endogenously generated by arteries. When the CRP mRNA levels of plaque tissue, normal artery, and liver were compared in the same cases, plaque levels were 10.2-fold higher than normal artery and 7.2-fold higher than liver. By Western blotting, we showed that the protein levels of CRP and complement proteins were also up-regulated in plaque tissue and that there was full activation of the classical complement pathway. By in situ hybridization, we detected intense signals for CRP and C4 mRNAs in smooth muscle-like cells and macrophages in the thickened intima of plaques. By immunohistochemistry we showed co-localization of CRP and the membrane attack complex of complement. We also detected up-regulation in plaque tissue of the mRNAs for the macrophage markers CD11b and HLA-DR, as well as their protein products. We showed by immunohistochemistry macrophage infiltration of plaque tissue. Because CRP is a complement activator, and activated complement attacks cells in plaque tissue, these data provide evidence of a self-sustaining autotoxic mechanism operating within the plaques as a precursor to thrombotic events.

Polymorphisms in inflammatory genes and the risk of Alzheimer disease.

Abstract: The concept of inflammation as a major factor in Alzheimer disease (AD) has heretofore been based on postmortem findings of autodestructive changes associated with the lesions coupled with epidemiological evidence of a protective effect of anti-inflammatory agents. Now there is evidence that the risk of AD is substantially influenced by a total of 10 polymorphisms in the inflammatory agents interleukin 1alpha, interleukin 1beta, interleukin 6, tumor necrosis factor alpha, alpha(2)-macroglobulin, and alpha(1)-antichymotrypsin. The polymorphisms are all common ones in the general population, so there is a strong likelihood that any given individual will inherit 1 or more of the high-risk alleles. The overall chances of an individual developing AD might be profoundly affected by a "susceptibility profile" reflecting the combined influence of inheriting multiple high-risk alleles. Since some of the polymorphisms in question have already been linked to peripheral inflammatory disorders, such as juvenile rheumatoid arthritis, myasthenia gravis, and periodontitis, associations between AD and several chronic degenerative diseases may eventually be demonstrated. Such information could lead to strategies for therapeutic intervention in the early stages of such disorders.

Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick's disease, corticobasal degeneration and progressive supranuclear palsy.

Abstract: We investigated isoform composition of aggregated tau protein in brains with Pick's disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) by immunoblot analysis of sarkosyl-insoluble fractions of brain homogenates. We also examined the adjacent brain tissues immunohistochemically with a rabbit antibody, Ex10, which specifically recognizes exon 10 of tau. The Ex10 recognizes tau isoforms with four microtubule-binding repeats (4Rtau) but not those with three microtubule-binding repeats (3Rtau). Sarkosyl-insoluble tau from the brains of patients with CBD and PSP consisted of 4Rtau. Insoluble tau from the PiD brains contained both 3Rtau and 4Rtau, where 3Rtau predominated over 4Rtau. In brain tissues of CBD and PSP, Ex10 immunostained all neuronal and glial tau-positive structures. They included pre-tangles, astrocytic plaques, tuft-shaped astrocytes, and oligodendroglial coiled bodies. In PiD brains, astrocytic inclusions were also positive for 4Rtau. However, the majority of, if not all, Pick bodies and oligodendroglial tau inclusions were negative for 4Rtau. Such results suggest that, in neurons and oligodendroglia, tau isoforms involved in the pathological processes differ between CBD/PSP and PiD, and are thus disease specific. This contrasts with the astrocytic tau isoforms that accumulate similarly in all three disorders.

Complement Components, but Not Complement Inhibitors, Are Upregulated in Atherosclerotic Plaques

Abstract: —Complement activation occurs in atherosclerotic plaques. The capacity of arterial tissue to inhibit this activation through generation of the complement regulators C1 inhibitor, decay accelerating factor, membrane cofactor protein (CD46), C4 binding protein (C4BP), and protectin (CD59) was evaluated in pairs of aortic atherosclerotic plaques and nearby normal artery from 11 human postmortem specimens. All 22 samples produced mRNAs for each of these proteins. The ratios of plaque versus normal artery pairs was not significantly different from unity for any of these inhibitors. However, in plaques, the mRNAs for C1r and C1s, the substrates for the C1 inhibitor, were increased 2.35- and 4.96-fold, respectively, compared with normal artery; mRNA for C4, the target for C4BP, was elevated l.34-fold; and mRNAs for C7 and C8, the targets for CD59, were elevated 2.61- and 3.25-fold, respectively. By Western blotting and immunohistochemistry, fraction Bb of factor B, a marker of alternative pathway activation, was barely detectable in plaque and normal arterial tissue. These data indicate that it is primarily the classical, not the alternative pathway, that is activated in plaques and that key inhibitors are not upregulated to defend against this activation.

A clinical and pathological study of motor neurone disease on Guam.

Abstract: Despite over 40 years of intensive study, the cause of the high incidence of motor neurone disease (MND) on Guam, and the relationship between this disease and MND seen in the rest of the world are still uncertain. We present a series of 45 cases of Guamanian MND, which reaffirm the clinical similarity between this disease and MND seen in other countries. However, the occurrence of MND among the indigenous Chamorros of Guam is distinguished by four factors: (i) high prevalence; (ii) frequent familial occurrence; (iii) co-occurrence with the parkinsonism-dementia complex (PDC); and (iv) association with an unusual and distinctive linear retinopathy termed Guam retinal pigment epitheliopathy (GRPE). These distinguishing factors were not present in four non-Chamorros who resided on Guam when their MND symptoms occurred. Pathologically, the classical features of MND were seen in Guamanian Chamorro cases including ubiquitin inclusions. Neurofibrillary tangles were frequently seen. The neurofibrillary tangles appeared in the same distribution as described in the PDC but, unlike classical PDC, they were not usually associated with cell loss and occurred less frequently. While neurofibrillary tangle formation and the clinicopathological syndrome of MND may occur in parallel, observations from this series suggest that pathologically classical MND on Guam may occur independently of neurofibrillary degeneration and the clinical features of PDC.

3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA in Alzheimer and control brain.

Abstract: Statins are widely used pharmaceutical agents which lower plasma cholesterol by inhibiting the rate controlling enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. One epidemiological study suggests that statin therapy may provide protection against Alzheimer disease (AD). The aim of the present study was to determine the relative expression of HMG-CoA reductase mRNAs in various areas of brain as well as in peripheral organs and to compare values in AD and control cases. High levels of the mRNA were found in all areas of brain but no obvious differences were found between AD and controls. We conclude that brain has a robust capacity to synthesize cholesterol which appears to be unaffected by AD pathology.

Chronic inflammation in Alzheimer's disease offers therapeutic opportunities.

Abstract: Postmortem studies have revealed a state of chronic inflammation in affected regions of the brain in Alzheimer’s disease (AD). Chronic inflammation can be damaging to host cells and the brain may be particularly vulnerable as neurons are not replaced. Evidence suggests that the inflammation is killing neurons in AD brain, so anti-inflammatory agents might slow the process of the disease. More than 20 epidemiological studies have shown that persons taking nonsteroidal anti-inflammatory drugs (NSAIDs) have a greatly reduced incidence of AD. In one clinical trial, indomethacin appeared to halt the progression of memory loss in AD patients. NSAIDs inhibit synthesis of prostaglandins, which are fringe players in the inflammatory process. Agents that would block the more important actors, such as the complement system, activated microglia and inflammatory cytokines, might have important therapeutic benefits in AD as well as in other conditions, such as heart disease and stroke, where inflammation also plays a d...

The involvement of glial cell-derived reactive oxygen and nitrogen species in Alzheimer’s disease

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by adult-onset progressive dementia and mainly affects the elderly. Pathologically, the brains of AD patients are characterized by the presence of neurofibrillary tangles (NFTs), amyloid β peptide (Aβ)-containing senile plaques (SPs) and synaptic and neuronal cell loss. Most research on AD has focused on the mechanisms that result in the formation of these insoluble NFTs and SPs [1 2]. NFTs represent the insoluble filamentous remnants of the cytoskeleton of affected neurons, with a major component being phosphorylated forms of the microtubule-associated protein tau. SPs primarily contain aggregated Aβ peptide fragments derived from the amyloid precursor protein (APP). In AD brains, both SPs and NFTs, as well as vulnerable neurons, have been shown to undergo a number of modifications indicative of ongoing oxidative stress [3-12].

COX-2 and ALS.

Abstract: (2001). COX-2 and ALS. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders: Vol. 2, No. 3, pp. 121-122.

Complement, neuroinflammation and neuronal degeneration in Alzheimer disease

Abstract: It is now established that the lesions of Alzheimer disease (AD) are characterized by the presence of a broad spectrum of inflammatory molecules. They include complement proteins and their regulators, inflammatory cytokines, acute phase reactants and numerous proteases and protease inhibitors [1,2]. Several of these inflammatory products are neurotoxic and may contribute in a major way to the progressive neuronal loss of AD. Probably the most dangerous to host tissue is the complement system. It can be activated in vitro by several molecules found in AD lesions, including β-amyloid protein and C-reactive protein. Activated complement fragments richly decorate AD lesions. The membrane-attack complex of the complement is observed attached to damaged neurites. Many activated microglia are also seen clustering around AD lesions. Like all phagocytes, activated microglia produce large amounts of free radicals, glutamate and other potentially neurotoxic compounds. This is a local rather than a systemic immune reaction, with the brain cells making the inflammatory components [2]. The hypothesis that chronic inflammation may be contributing to neuronal death in AD is supported by epidemiological studies indicating that patients taking anti-inflammatory drugs, particularly of the nonsteroidal type, have a substantially reduced risk of AD [3]. In a pilot, 6-month, double-blind clinical trial, indomethacin appeared to arrest the disease [4].