Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain.

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Recent studies indicate that the proinflammatory enzyme cyclooxygenase (COX)-2, an enzyme involved in inflammatory cascades but also normal neuronal activities, is elevated in the brain and spinal cord of amyotrophic lateral sclerosis (ALS) patients and ALS mouse model systems. On the basis of this evidence, we explored the impact of COX-2 inhibition on the onset and progression of ALS-like disease in the G93A human superoxide dismutase (SOD)1 mouse model of ALS. We found that prophylactic administration of nimesulide, a preferential COX-2 inhibitor, in the feed resulted in a significant delay in the onset of ALS type motor impairment. This delay of ALS symptomatology temporally overlapped with the inhibition of prostaglandin E2 elevation in the spinal cord of SOD1-G93A transgenic mice relative to untreated SOD1-G93A controls. This study strongly supports a role for COX-2 in the pathophysiology of ALS and provides the first experimental evidence that prophylactic treatment with COX-2 inhibitors can significantly delay the onset of motor dysfunction in the SOD1-G93A transgenic mouse model of ALS.

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.

In previous studies we found that overexpression of the inducible form of cyclooxygenase, COX-2, in the brain exacerbated beta-amyloid (A beta) neuropathology in a transgenic mouse model of Alzheimer's disease. To explore the mechanism through which COX may influence A beta amyloidosis, we used an adenoviral gene transfer system to study the effects of human (h)COX-1 and hCOX-2 isoform expression on A beta peptide generation. We found that expression of hCOXs in human amyloid precursor protein (APP)-overexpressing (Chinese hamster ovary (CHO)-APPswe) cells or human neuroglioma (H4-APP751) cells resulting in 10-25 nM prostaglandin (PG)-E2 concentration in the conditioned medium coincided with an approximately 1.8-fold elevation of A beta-(1-40) and A beta-(1-42) peptide generation and an approximately 1.8-fold induction of the C-terminal fragment (CTF)-gamma cleavage product of the APP, an index of gamma-secretase activity. Treatment of APP-overexpressing cells with the non-selective COX inhibitor ibuprofen (1 microM, 48 h) or with the specific gamma-secretase inhibitor L-685,458 significantly attenuated hCOX-1- and hCOX-2-mediated induction of A beta peptide generation and CTF-gamma cleavage product formation. Based on this evidence, we next tested the hypothesis that COX expression might promote A beta peptide generation via a PG-E2-mediated mechanism. We found that exposure of CHO-APPswe or human embryonic kidney (HEK-APPswe) cells to PG-E2 (11-deoxy-PG-E2) at a concentration (10 nM) within the range of PG-E2 found in hCOX-expressing cells similarly promoted (approximately 1.8-fold) the generation of the CTF-gamma cleavage product of APP and commensurate A beta-(1-40) and A beta-(1-42) peptide elevation. The study suggests that expression of COXs may influence A beta peptide generation through mechanisms that involve PG-E2-mediated potentiation of gamma-secretase activity, further supporting a role for COX-2 and COX-1 in Alzheimer's disease neuropathology.