Showing papers by "Patrick L. McGeer published in 1999"

Up-regulated production and activation of the complement system in Alzheimer's disease brain.

Abstract: We used reverse transcriptase-polymerase chain reaction and Western blotting techniques to measure the levels of complement mRNAs and their protein products in Alzheimer's disease (AD) brain compared with non-AD brain. mRNAs for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 were detected in the 11 regions of brain that were investigated. The mRNA levels were markedly up-regulated in affected areas of AD brain. In the entorhinal cortex, hippocampus, and midtemporal gyrus, which had dense accumulations of plaques and tangles, C1q mRNA was increased 11- to 80-fold over control levels, and C9 mRNA 10- to 27-fold. These levels were substantially higher than in the livers of the same cases. Western blot analysis of AD hippocampus established the presence of all of the native complement proteins as well as their activation products C4d, C3d, and the membrane attack complex. These data indicate that high levels of complement are being produced in affected areas of AD brain, that full activation of the classical complement pathway is continuously taking place, and that this activation may be contributing significantly to AD pathology.

Inflammation of the brain in Alzheimer's disease: implications for therapy.

Abstract: We briefly describe the similarities and differences between a systemic and a local immune reaction and review the evidence that the latter occurs in Alzheimer's disease (AD) brains. The evidence comes mainly from studies on the comple- ment system, microglia, and cytokines, all of which are important actors in the inflammatory process. The evidence is now overwhelming that the comple- ment proteins and many of the mediators of inflam- mation are produced locally by brain cells. We will mention briefly the many epidemiological studies indicating that the use of anti-inflammatory drugs reduces the incidence and slows the progress of AD. Mention will also be made of some recent work on animal models of possible relevance to AD and inflammation. J. Leukoc. Biol. 65: 409-415; 1999.

Brain inflammation in Alzheimer disease and the therapeutic implications.

Abstract: Immunohistochemical studies suggested the existence of a chronic inflammatory condition in affected regions of the brain in Alzheimer disease (AD). Since inflammation can be damaging to host tissue, it was hypothesized that antiinflammatory drugs might inhibit both the onset and the progression of AD. This hypothesis is supported by a number of epidemiological studies suggesting that the prevalence of AD in persons is reduced by 40 - 50% in persons using antiinflammatory drugs. In one small pilot trial in early AD, the nonsteroidal antiinflammatory drug indomethacin appeared to halt the progressive memory loss. Immunohistochemical and molecular biological studies on immune system components in AD brain are revealing the complexities of the innate immune reaction. This very complexity may offer points of therapeutic intervention for new types of antiinflammatory agents. The complement system, microglia and cytokines are key components. This review summarizes the present state of knowledge on the immune system elements found in AD brain.

Occurrence of the diffuse amyloid β‐protein (Aβ) deposits with numerous Aβ‐containing glial cells in the cerebral cortex of patients with Alzheimer's disease

Abstract: Diffuse amyloid β-protein (Aβ) deposits with numerous glial cells containing C-terminal Aβ fragments occur in the cerebral cortex of patients with Alzheimer's disease. By using a panel of antibodies specific for various epitopes in the Aβ peptide, we have investigated the immunohistochemical nature of the diffuse Aβ deposits. The extracellular material contains Aβ with a C-terminus at residue valine40 (Aβ40) as well as residues alanine42/threonine43 (Aβ42). The N-termini include aspartate1, pyroglutamate3, and pyroglutamate11, with pyroglutamate3 being dominant. Microglia and astrocytes in and around these deposits contain intensely staining granules. Most of these granules are negative for antibodies to the N-terminally located sequences of Aβ. These include 6E10 (Aβ1–17), 6F/3D (Aβ8–17), and the N-terminal antibodies specific to aspartate1, pyroglutamate3, and pyroglutamate11. The C-termini of intraglial Aβ are comparable with those of the extracellular deposits. The microglia and astrocytes have quiescent morphology compared with those associated with senile plaques and other lesions such as ischemia. Complement activation in these deposits is not prominent and often below the sensitivity of immunohistochemical detection. Although factors which may cause this type of deposit remain unclear, lack of strong tissue responses suggests that these deposits are a very early stage of Aβ deposition. They were found only inconsistently and were absent in a number of cases examined in this study. Further analysis of these deposits might provide important clues regarding the accumulation and clearance of Aβ in Alzheimer's disease brain. GLIA 25:324–331, 1999. © 1999 Wiley-Liss, Inc.

Neurodegenerative diseases of Guam: analysis of TAU.

Abstract: Mutations in the tau gene have been described in families affected by frontotemporal dementia with parkinsonism linked to chromosome 17. The authors performed a genetic and biochemical analysis of this gene and its product in the parkinsonism dementia complex of Guam, a disorder characterized by the extensive formation of neurofibrillary tangles. The tau gene is not a primary cause of the parkinsonism dementia complex of Guam.

Preconditioning reduces tissue complement gene expression in the rabbit isolated heart.

Abstract: Both preconditioning and inhibition of complement activation have been shown to ameliorate myocardial ischemia-reperfusion injury. The recent demonstration that myocardial tissue expresses compleme...