Downregulation of neuronal cyclooxygenase-2 expression in end stage Alzheimer's disease.

Nonsteroidal anti-inflammatory drugs (NSAIDs) appear to delay the onset of Alzheimer's disease (AD). NSAIDs inhibit cyclooxygenase (COX), of which two isoforms exist. We report decreased neuronal COX-2 expression in AD subjects relative to nondemented controls using qualitative analysis of COX-2 immunoreactivity and quantification of COX-2 positive neurons in different hippocampal subfields. These changes also occurred in subjects with other dementia and thus may not be disease specific. The proportion of COX-2 positive neurons decreased in subjects with clinical dementia rating (CDR) 5 but not CDR 4, suggesting that this was a late event in the course of the disease. Furthermore, COX-2 was not preferentially associated with paired helical filament immunoreactivity, a marker of neuronal pathology. COX-2 immunoreactivity was also observed in astrocytes and cerebrovasculature. Indeed, the density of COX-2 immunopositive astrocytes was increased in AD temporal cortex. Based on our findings, it is unlikely that neuronal COX-2 contributes to pathology in end stage AD; however, COX-2 in other cell types may participate in the inflammation-related response associated with the disease.

Cyclooxygenases in the central nervous system: implications for treatment of neurological disorders.

Recognition of two isoforms of cyclooxygenase and reports that nonsteroidal anti-inflammatory drugs may be beneficial in devastating neurological conditions such as Alzheimer's disease have led to increased interest in cyclooxygenase function in the nervous system. In the present paper we review current data on the multiplicity of cyclooxygenase and prostaglandin mediated effects in the central nervous system (CNS). We discuss CNS cells types, including neurons, glia, and cerebrovascular elements, where cyclooxygenases-1 and -2 are expressed under normal conditions or can be induced by physiological or pathological stimuli. We also address physiological processes such as pain sensitization, CNS inflammation and fever induction that are regulated or modified by cyclooxygenase activity. Finally, we describe potential roles of cyclooxygenase in neurological diseases and rationales for nonsteroidal anti-inflammatory drug use in the treatment of neurodegenerative disorders, stroke and CNS injury.

Cyclooxygenase-1 in human Alzheimer and control brain: quantitative analysis of expression by microglia and CA3 hippocampal neurons.

Epidemiological and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase (COX) slow the progression and delay the onset of Alzheimer disease (AD). Two isoforms of cyclooxygenase have been identified. Although much effort has recently been focused on the inducible COX-2 isoform, little is known about COX-1 expression in human brain. We report that COX-1 message and immunoreactivity are localized to human hippocampal CA3 and CA4 neurons, granular neurons in neocortical layer IV, and occasional cortical pyramidal neurons. Quantitative in situ hybridization showed no differences between COX-1 mRNA levels in control and AD CA3 hippocampal neurons. COX-1 immunoreactivity was also present in microglial cells in gray and white matter in all brain regions examined. COX-1 appeared to be expressed in microglial cells regardless of their activation state as determined by HLA-DR immunostaining. However, COX-1 immunopositive microglia were found in association with Abeta plaques, and the density of COX-1 immunopositive microglia in AD fusiform cortex was increased. This pattern suggests an overall increase of COX-1 expression in AD. Currently used NSAIDs inhibit both isoforms of cyclooxygenase. The present study shows that COX-1 is widely expressed in human brain, and raises the possibility that COX-1 may contribute to CNS pathology.