Inflammation And The Clinical Progression Of Alzheimers Disease Dementia

Super Memory Formula

Cure Dementia Forever

Get Instant Access

Prior studies have shown that COX-2, an enzyme involved in inflammatory mechanisms and neuronal activities (reviewed in Pasinetti, 1998), is upregulated in the AD brain and may represent a therapeutic target for antiinflammatory treatments (Ho et al., 1999). COX exists in two isoforms, coded by distinct genes on different chromosomes (Kujubu et al., 1991; Cao et al., 1995; O'Banion et al., 1992). The two isoforms show about 50% homology and have similar catalytic activity, but are physiologically distinct. COX-2 is inducible in inflammatory cells in response to inflammatory signals, such as cytokines and lipopolysaccharides, and is downregulated by glucocorticoids. In contrast, COX-1 expression is generally constitutive. It thus appears that COX-2 mediates inflammatory activity, while COX-1 has housekeeping functions, including gastric cytoprotection and platelet aggregation (Table 35.1).

Recent evidence suggests that different indices of classical inflammatory cascades may have distinct associations with different phases of the clinical progression of AD, as reflected in the clinical dementia rating (CDR) (Luterman et al., 2000). For example, COX-2 (but not COX-1) expression in the neurons of the hippocampal formation, a brain region at risk for AD neurodegeneration, may be a predictor of progression of early AD before neurodegeneration occurs (Ho et al., 2001, in press). Surprisingly, and in contrast to COX-2, other classical markers of inflammatory neurodegeneration,

Table 35.1

COX-1 Brain

. Expression in brain but not regulated in response to experimental neurodegeneration Expression

. Chromosome 9 (q32 q33.3) . Constitutive expression

. Stimulated by growth factor in selected cells Function

. Prostaglandin formation for housekeeping functions . Gastric cytoprotection . Vascular homeostasis . Normal renal maintenance

COX-2 Brain

. Expressed primarily in neurons

. Regulated in response to experimental neurodegeneration . Localized in dendrites Expression

. Induced expression by inflammatory mediators, mitogens; elevated expression in tumors . Transcription inhibited by TGFß1 Function

. Inflammation . Cellular differentiation . Mitogenesis such as interleukin-6 (IL-6) and transforming growth factor p1 (TGFp1) (Luterman et al., 2000), HLA-DR immunopositive reactive microglia, and complement components gene expression (Xiang and Pasinetti, 2000) showed increased expression, but only at the latest stages of AD dementia (Figure 35.1).

The evidence showing elevation of COX-2 protein content in neurons of the hippocampal formation early in AD dementia suggests that independent segments of inflammatory cascades may play important and possibly independent roles in separate phases of the disease, ultimately influencing the progression of AD dementia. Given these findings, antiinflammatory drugs selected for studies of AD patients at a particular clinical stage should be selected based on their activity against the inflammatory processes most pronounced at that stage; for example, using COX-2 inhibitors in the early phase of AD. Thus, the identification of specific early markers involved in destructive brain inflammation would provide critically important selection criteria and/or possible co-variance for clinical trials of antiinflammatory drugs.

Complications Alzheimer Disease

Figure 35.1. Inflammatory markers and clinical progression of Alzheimer's disease dementia

Normal Questionable Mild Moderate Severe

Figure 35.1. Inflammatory markers and clinical progression of Alzheimer's disease dementia

Major efforts are now under way to determine whether COX inhibitors can help control the destructive progression of AD. Large National Institutes of Health (NIH)-supported trials are evaluating whether selective COX-2 inhibitors, or low-dose non-selective NSAIDs, can delay the diagnosis of AD. Industry-sponsored trials of selective COX-2 inhibitors currently target individuals with mild cognitive impairment. Additional trials are in the planning stages as new COX-2 inhibitors continue to be developed. Further elucidation of the role of COX-2 (and COX-1) in various clinical stages of AD, defined by the clinical dementia rating, will clearly aid the clinical design of such trials. As discussed above, the elevation of neuronal COX-2 expression during the early phase (mild dementia) of the clinical progression of AD dementia might set favorable conditions for later inflammatory neurodegenerative conditions. This would be consistent with the apparent early upregulation of COX-2 in neurons of the AD brain, prior to an elevation of cytokine (e.g. IL-6, TGFpj) expression (Luterman et al., 2000) and microglial activity (Xiang and Pasinetti, submitted). Moreover, recent evidence suggests that AD patients with a history of NSAID use perform better on neuropsychological test scores than non-users, independently of AD neuropathology (Halliday et al., 2000).

Was this article helpful?

0 0
All About Alzheimers

All About Alzheimers

The comprehensive new ebook All About Alzheimers puts everything into perspective. Youll gain insight and awareness into the disease. Learn how to maintain the patients emotional health. Discover tactics you can use to deal with constant life changes. Find out how counselors can help, and when they should intervene. Learn safety precautions that can protect you, your family and your loved one. All About Alzheimers will truly empower you.

Get My Free Ebook


Post a comment