Cyclooxygenase-2 Promotes Amyloid Plaque Deposition in a Mouse Model of Alzheimer's Disease Neuropathology

Abstract

Several epidemiologic studies have reported that cyclooxygenase (COX) inhibitors prevent/delay the onset of Alzheimer's disease (AD). Recent experimental studies suggest that these compounds can also diminish amyloidβ (Aβ) neuropathology in rodent models of AD. To explore the relationship of COX expression to Aβ neuropathology, we crossed mice expressing both mutant amyloid precursor protein [K670N/M671L (APP swe )] and mutant PS1 (A246E) with mice expressing human COX-2 selectively in neurons. We show here that human COX-2 expression in APP swe /PS1/COX-2 mice induces potentiation of brain parenchymal amyloid plaque formation and a greater than twofold increase in prostaglandin E 2 production, at 24 months of age. This increased amyloid plaque formation coincided with a preferential elevation of Aβ 1-40 and Aβ 1-42 with no change in total amyloid precursor protein (APP) expression/content in the brain. Collectively these data suggest that COX-2 influences APP processing and promotes amyloidosis in the brain. COX-2Amyloid Alzheimer's disease Inflammation A large number of epidemiological studies have indi-(14,21) have shown that COX-2 expression is elevated in the AD brain and that this elevation is corre-cated that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent or delay the clinical fea-lated with the severity of brain amyloid plaque pathology (6). Additionally, a recent study found a tures of Alzheimer's disease (AD) (7,13,18). However, recent therapeutic studies with both cyclooxygenase preferential loss of hippocampal COX-2-immunopositive neurons in the brains of AD patients suffering (COX)-inhibiting NSAIDs and steroids could not confirm this epidemiological evidence (9).severe dementia (22). However, recent evidence indicates that nonselective COX, rather than selective The pharmacological activity of NSAIDs is generally attributed to the inhibition of COX, a rate-limit-COX-2-specific inhibitors, has been found to influence amyloid precursor protein (APP) processing. ing enzyme necessary for the production of prostaglandins (PGs). COX-2 is the inducible form of COX Thus, the characterization of COX activities in the brain and their role in AD amyloidosis is receiving a and is involved in inflammatory responses but also neuronal functions (22). We (5,6,15) and others great deal of attention.

Deletion of the Prostaglandin E2EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

“…Our findings suggest a potential mechanism for the antiamyloid and proamyloid properties of NSAIDs and COX-2 overexpression, respectively, in transgenic models of mutant APP (Lim et al, 2001;Jantzen et al, 2002;Xiang et al, 2002;. The effects of EP2 receptor deletion may also be relevant to the preventive effects of chronic NSAID use against the development of AD (McGeer et al, 1996;Stewart et al, 1997;in t' Veld et al, 2001), in which decreased COX activity might lead to lower levels of downstream PGE 2 production and EP2 receptor signaling.…”

A Randomized, Double-Blind, Study of Rofecoxib in Patients with Mild Cognitive Impairment

“…We cannot exclude the possibility that rofecoxib might accelerate conversion of MCI patients to AD, although this possibility would be at variance with the prior epidemiological and clinical data cited above, as well as the body of experimental evidence suggesting that COX-2 inhibition might attenuate neuronal death in several disease states including Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, in addition to AD (Andreasson et al, 2001;Jain et al, 2002;Xiang et al, 2002;Giovannini et al, 2003;Scali et al, 2003;Teismann et al, 2003;Qin et al, 2003;Consilvio et al, 2004;Rose et al, 2004). The early onset of the treatment difference (and the lack of progressive widening of the difference over the course of the trial) further argues against a direct effect of rofecoxib on the underlying pathophysiology in AD.…”

Brain Inflammation and Alzheimer's-Like Pathology in Individuals Exposed to Severe Air Pollution

“…Aβ42 accumulation may be a consequence of the increase in COX2 expression. Neuron-specific ectopic expression of human COX2 in the brain of a mouse model of Alzheimer's disease increased β-amyloid plaque formation and elevated Aβ40 and Aβ42 with no change in total APP, suggesting that COX2 influences APP processing (Xiang et al, 2002). Using an adenoviral gene transfer system to study the effects of COX1 and COX2 on β-amyloid generation, Qin and coworkers (2003) found that COXs promote Aβ generation via a PG-E2-mediated activation of γ -secretase, the membrane proteinase that generates Aβ40 and Aβ42.…”