Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration.

We evaluated entorhinal cortex and superior frontal gyrus for hallmarks of Alzheimer's disease (AD) pathology, including inflammation, in three patient sets: AD patients, nondemented elderly patients with few or no neurofibrillary tangles (NFTs) and amyloid beta peptide (A beta) deposits, i.e. normal controls (NC), and nondemented elderly patients with profuse entorhinal cortex NFTs and neocortical A beta deposits, i.e. high pathology controls (HPC). Membrane attack complex (C5b-9) immunoreactivity and immune activation of microglia (MHCII expression) were used as general markers for inflammation. Compared to NC patients, AD patients exhibited significant cortical synapse loss, A beta deposition, NFT formation, and inflammation. HPC patients also had significantly elevated A beta deposition and NFT formation, but there was no evidence of synapse loss and little or no evidence of inflammation. Across patients and brain regions the measures of inflammation each accounted for significant percentages of the variance in synaptophysin immunoreactivity and each was more highly correlated with synapse estimates than NFT formation or A beta deposition.

Inflammation and Alzheimer's disease pathogenesis.

Appreciation of the role that inflammatory mediators play in Alzheimer's disease (AD) pathogenesis continues to be hampered by two related misconceptions. The first is that to be pathogenically significant a neurodegenerative mechanism must be primary. The second is that inflammation merely occurs to clear the detritis of already existent pathology. The present review addresses these issues by showing that 1) inflammatory molecules and mechanisms are uniquely present or significantly elevated in the AD brain, 2) inflammation may be a necessary component of AD pathogenesis, 3) inflammation may be sufficient to cause AD neurodegeneration, and 4) retrospective and direct clinical trials suggest a therapeutic benefit of conventional antiinflammatory medications in slowing the progress or even delaying the onset of AD.

Complement activation by beta-amyloid in Alzheimer disease.

Alzheimer disease (AD) is characterized by excessive deposition of the beta-amyloid peptide (beta-AP) in the central nervous system. Although several lines of evidence suggest that beta-AP is neurotoxic, a mechanism for beta-AP toxicity in AD brain remains unclear. In this paper we provide both direct in vitro evidence that beta-AP can bind and activate the classical complement cytolytic pathway in the absence of antibody and indirect in situ evidence that such actions occur in the AD brain in association with areas of AD pathology.

Molecular, cellular, and pathologic characterization of HLA-DR immunoreactivity in normal elderly and Alzheimer's disease brain.

Previous studies have suggested that markers of immune function may be present in brain. We have characterized one of the most important of these markers, the human major histocompatibility complex antigen HLA-DR, at molecular, cellular, and pathologic levels. The results show that an antigen with the correct molecular weight for HLA-DR and the appropriate immunoreactivity for HLA-DR monoclonal antibodies is present in nondemented elderly (ND) and Alzheimer's disease (AD) brain tissue. HLA-DR immunoreactivity is profusely expressed by brain microglia, often expressed by lymphocytes within the neuropil, rarely expressed by astrocytes, and not expressed by neurons or oligodendrocytes. Pathologically, HLA-DR-like staining in ND patients is confined primarily to white matter nonreactive or resting microglia. In AD patients, both white matter and gray matter are stained, and HLA-DR-positive reactive microglia predominate. Virtually all senile or neuritic plaques are densely HLA-DR immunoreactive: at the plaque core staining intensity is elevated as much as 50-fold, dropping to background at the plaque margin.

Epidermal growth factor receptor expression in demented and aged human brain.

Immunoreactivity to epidermal growth factor receptor (EGFR) was present in the brain vasculature of 13/13 demented elderly patients, but absent in 9/11 non-demented elderly patients. Of the two positive non-demented patients, one had significant Alzheimer's pathology and the other spinal carcinoma. Ultrastructurally, EGFR is localized to the lumenal surface of endothelial cells.

Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease.

HLA-DR is a class II major histocompatibility complex antigen which in the periphery confers antigen presenting capability. We have previously shown that this marker is profusely expressed in cortex of elderly and Alzheimer's disease (AD) patients, as is the receptor for the lymphokine interleukin-2. We now report presence of additional immune-related antigens in AD, and distributional differences from normal elderly controls. In gray matter, HLA-DR immunoreactivity is normally sparse, except in AD where it co-localizes with virtually all neuritic plaques. HLA-DR positive T cells can be demonstrated in Alzheimer's disease brain tissue, as can instances of apposition between putative brain microglia and T cells. In addition, cells with the morphologic characteristics of astrocytes label for natural killer cell antigen (Leu-11), and apparent lymphocytes bearing T helper and T cytotoxic/suppressor cell antigens are observed. These and other data suggest that the glial proliferation and scavenger activity characteristic of Alzheimer's disease may occur in an immune context and may play an important role in the pathogenesis of the disorder.

Enzyme defects in hereditary porphyria.

Heme is an important prosthetic group for proteins concerned with energy metabolism. All cells in the body probably make heme, but nucleated erythroid and hepatic cells have been studied the most. Feedback control of heme formation differs in the red cells and in the liver. About eight enzymes have a place in the formation of heme. Defects in the enzyme pathways may be the result of genetic abnormalities and phenotypically occur as hereditary porphyrias. If the major defect occurs in the red cell line, erythropoietic porphyrias occur; if the liver has the major defect, than hepatic porphyrias are present. There are probably three erythropoietic porphyrias and four hepatic porphyrias which are genetically determined. However, some are not clearly classified,--with erythropoietic protoporphyria involving hepatic and erythroid cells and porphyria cutanea tarda not being a clear cut genetic abnormality, at least some of the time. Elucidation of the genetic enzymatic defects introduces new diagnostic tools and also has led to at least one revolutionary new treatment for some hepatic porphyrias.

Amniotic fluid phospholipids measured by continuous-development thin-layer chromatography.

We describe a one-dimensional thin-layer chromatographic system for separation of amniotic fluid phosphatidylcholine, sphingomyelin, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, and phosphatidylethanolamine in amniotic fluid. We utilize short-bed continuous development and "high performance" thin-layer chromatography. Phospholipids are detected with an antimony molybdate staining reagent and quantitated by transmittance densitometry. This system is more sensitive to changes in lecithin/sphingomyelin ratios than are planimetric evaluations.

Interpretation of cerebrospinal fluid proteins by gel electrophoresis.

The use of polyacrylamide gel electrophoresis (PAGE) for the separation of proteins in cerebrospinal fluid (CSF) results in greater definition than does a "routine" method such as cellulose acetate electrophoresis. Unconcentrated CSF is easily separated into as many as 18 bands by the use of PAGE. By means of a modified PAGE method described in this paper, unconcentrated and untreated CSF is quickly and conveniently analyzed for protein constituents. This modification involves a continuous buffer environment, a pore-size concentration gradient and CSF in amounts of 0.1 to 0.4 ml. Sucrose addition is not necessary in this procedure. Whereas most central nervous system (CNS) disease states do not yield consistently distinctive protein patterns, some diseases, such as vascular disease, infectious meningitis and some metastatic tumors, yield significantly altered patterns. It is suggested that the chief value of CSF protein electrophoresis at the present time is to follow the course of a CNS disease.