20 Dec 2000

The molecular and genetic mechanisms involved in the initiation and progression of Alzheimer’s disease (AD) are poorly understood. One emerging player in the proinflammatory cycle operating in AD brain is cyclooxygenase-2 (COX)-2, an inducible prostaglandin synthase which has been repeatedly shown [independently by several laboratories] to be overexpressed in association neocortex and hippocampus afflicted with AD. Because of its pivotal importance in mediating brain inflammatory reactions, COX-2 has been a pharmacological target in human AD therapeutics. Selective nonsteroidal anti-inflammatory drugs (NSAIDS) which specifically inhibit COX-2 inhibitors, i.e., the COX-bs (rofecoxib, celecoxib, etc.) are currently being developed and used in clinical trials.

Pasinetti’s group (299.14) reported that the intensity of COX-2 gene expression in the CA3 and CA2 (but not CA-1) hippocampal pyramidal layers in AD brain increases in parallel with disease progression, and more specifically as AD progressed from questionable (CDR1) to mild clinical dementia (CDR3), [i.e., from a clinical dementia rating (CDR) which is on a scale of CDR0 (no dementia) to CDR5 (very severe dementia)]. COX-2 expression was found to be preferentially elevated in neuronal cells. At CDR5 COX-2 gene expression was increased in all three hippocampal regions (see Ho et al., 2000).

Experiments using triply transgenic mice (APPswe/PS1-A246E?hCOX-2; amyloid precursor protein-human presenilin-1-COX-2) suggested that COX-2 may have an influence on how Aβ peptide is processed. Importantly, the elevation in COX-2 gene expression preceded elevations in cytokine IL-6 and TGF-B1 gene expression at advanced CDR stages, suggesting that the upregulation of COX-2 gene expression is an early or preinflammatory event in AD staging. Pasinetti’s data therefore supported the ideas that (1) NSAIDs are efficacious because they, in part, may be exerting effects on COX-2 during the early stages of AD, (2) that specific inflammatory conditions have direct correlations with the clinical progression of AD, and (3) there is a strong correlation between internal markers in AD brain and the index of cognitive decline. Such considerations are therefore expected to be essential for the design of preventive treatment strategies.—Walter Lukiw

References: 299.14. Pasinetti GM. Brain inflammation as a function of clinical progression of Alzheimer's disease dementia: Implications for preventive anti-inflammatory strategies.