Abstract
Neuronal expression of cyclooxygenase-2 (COX-2) and cell cycle proteins is suggested to contribute to neurodegeneration during Alzheimer's disease (AD). The stimulus that induces COX-2 and cell cycle protein expression in AD is still elusive. Activated glia cells are shown to secrete substances that can induce expression of COX-2 and cell cycle proteins in vitro. Using post mortem brain tissue we have investigated whether activation of microglia and astrocytes in AD brain can be correlated with the expression of COX-2 and phosphorylated retinoblastoma protein (ppRb). The highest levels of neuronal COX-2 and ppRb immunoreactivity are observed in the first stages of AD pathology (Braak 0–II, Braak A). No significant difference in COX-2 or ppRb neuronal immunoreactivity is observed between Braak stage 0 and later Braak stages for neurofibrillary changes or amyloid plaques. The mean number of COX-2 or ppRb immunoreactive neurons is significantly decreased in Braak stage C compared to Braak stage A for amyloid deposits. Immunoreactivity for glial markers KP1, CR3/43 and GFAP appears in the later Braak stages and is significantly increased in Braak stage V-VI compared to Braak stage 0 for neurofibrillary changes. In addition, a significant negative correlation is observed between the presence of KP1, CR3/43 and GFAP immunoreactivity and the presence of neuronal immunoreactivity for COX-2 and ppRb. These data show that maximal COX-2 and ppRb immunoreactivity in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia. In contrast to in vitro studies, post mortem data do not support a causal relation between the activation of microglia and astrocytes and the expression of neuronal COX-2 and ppRb in the pathological cascade of AD.
Highlights
Cyclin dependent kinases (CDKs) and their inhibitors has been observed in post mitotic neurons in Alzheimer's disease (AD) [1,2]
In the midfrontal and temporal cortex phosphorylated retinoblastoma protein (ppRb) immunoreactivity can be most prominently detected in the nucleus of the large pyramidal neurons of layers III and V, and is rarely detected in neurofibrillary tangles
Recent studies have shown that neuronal cyclooxygenase-2 (COX-2) expression in AD parallels the expression of cell cycle proteins in neurons [6,7,8]
Summary
We observed colocalization of COX-2 with ppRb in neurons in the temporal cortex of AD and control cases [6]. These in vitro findings indicate that the activation of microglia may play an important role in the expression of COX-2 and cell cycle proteins in neurons. Cell cycle changes and increased neuronal COX-2 expression have been shown to be early events in AD [1,7,16,17].
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