Abstract
Epidemiological studies have suggested that the chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the relative risk of Alzheimer’s disease (AD). The possible neuroprotection by NSAIDs in AD is generally attributed to anti-inflammatory activity. An additional mode of drug action may involve anti-aggregation of β-amyloid (Aβ) peptides by commonly used NSAIDs. We utilized in vitro competition assays, autoradiography, and fluorescence microscopy with AD brain specimens to demonstrate concentration-dependent decreases in the binding of the in vivo molecular imaging probe, 2-(1-{6-[(2-[ 18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([ 18F]FDDNP), against ( S)-naproxen and ( R)- and ( S)-ibuprofen (but not diclofenac) to Aβ fibrils and ex vivo Aβ senile plaques. Conversely, in vitro amyloid dyes Congo Red and Thioflavine T were demonstrated in the same experiments not to bind to the FDDNP binding site. FDDNP and the NSAIDs that share the same binding site also exhibit anti-aggregation effects on Aβ peptides, suggesting that the shared binding site on Aβ fibrils and plaques may be a site of anti-aggregation drug action. Our results indicate for the first time the binding of select NSAIDs to plaques, specifically to the binding site of the molecular imaging probe [ 18F]FDDNP. Our understanding of the molecular requirements of FDDNP binding may help in the optimization of the Aβ anti-aggregation potency of experimental drugs. [ 18F]FDDNP has been used to image plaques in vivo with positron emission tomography (PET), and investigations into the influence of Aβ anti-aggregation on the risk-reduction effects of NSAIDs on AD could utilize [ 18F]FDDNP and PET in determining the occupancy rate of NSAIDs and experimental drugs in plaques in the living brain of AD patients.
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