Cyclooxygenase-1 and -2 in the Different Stages of Alzheimers Disease Pathology

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (A ) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD.The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar A deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar A deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

“…As in our results using AD model mice, previous studies with postmortem brain from AD patients showed an increase in COX-1-expressing microglia surrounding Ab plaques (5,6). In addition, COX-2 is expressed in neurons in the early phase of the disease but not in microglia or astrocytes (26).…”

High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease

“…It seems that amyloid-b peptide, which is derived from the longer amyloid precursor protein (APP), is the main stimulator of the inflammatory response found in the brain of AD patients (Sastre et al, 2008), resulting in the presence of activated microglia and astrocytes around neuritic plaques (Rodrigo et al, 2004) and increased levels of inflammatory mediators (Hoozemans et al, 2008). Some current hypotheses suggest that even peripheral chronic infections, such as periodontal episodes, may affect the onset and progression of AD (Kamer et al, 2008).…”

Changes in Cyclooxygenase-2 Immunoreactivity in the Hippocampus in a Model of Streptozotocin-Induced Type 1 Diabetic Rats

“…Cyclooxygenase (COX), a membrane-bound protein, is involved in inflammation, angiogenesis, colon cancer and Alzheimer's disease [8,11], and classified into two types, COX-1 and COX-2. Both isoenzymes convert arachidonic acid into multifunctional prostanoids.…”

“…Both isoenzymes convert arachidonic acid into multifunctional prostanoids. COX-2 enzyme is reported as a key player [11] in neuro-inflammation which is involved in most neurodegenerative disorders by eliciting neuronal death and influencing formation of new neurons [9]. In several tissues, mRNA level of COX-2 was studied and level in the brain was lowest [24], but its expression in brain was not the lowest [35].…”