Address for correspondence: Greg M. Cole, Greater Los Angeles Healthcare System, Veterans Administration Medical Center, 16111 Plummer St., Bldg. 7, Room A102, North Hills, CA 91343. Voice: 818-891-7711, ext. 9949; fax: 818-895-5835. gmcole{at}ucla.edu
Both oxidative damage and inflammation are elevated in brains
of Alzheimer's disease (AD) patients, but their pathogenic significance
remains unclear. The reduced AD risk associated with high intake
of both nonsteroidal anti-inflammatory drugs (NSAIDs) and antioxidants
suggests causal roles, but clinical trials in AD patients have
yielded only limited or negative results. To test the potential
efficacy and mechanisms of candidate approaches, we have explored
conventional and unconventional NSAIDs, antioxidants, and combined
NSAID/antioxidants in cell culture and animal models for AD
(including aging APPsw transgenic mice and soluble Aß
rodent infusion models). The conventional NSAID ibuprofen has
the strongest epidemiological support. At sustainable doses
designed to mimic protective consumption in the epidemiology,
ibuprofen reduces amyloid accumulation but suppresses a surprisingly
limited subset of inflammatory markers in APPsw transgenic mice.
Both Ab production (APP, ß- and
-secretases) and post-production
pathways (those affecting Aß aggregation or clearance:
e.g., IL-1 or
1ACT) are potentially involved in ibuprofen and
other NSAID anti-AD activities. The post-production pathways
are predictably shared with other seemingly protective NSAIDs,
including naproxen that do not lower Aß42
in vitro.
Using clinically feasible dosing, brain levels of NSAIDs appear
too low to implicate a number of pharmacological dose targets
that have been demonstrated
in vitro. Ibuprofen did not suppress
microglial markers related to phagocytosis. The putative anti-inflammatory
omega-3 fatty acid DHA had a profound impact on pathogenesis
but did not lower inflammation, while vitamin E was surprisingly
ineffective in reducing oxidative damage or amyloid in the aged
APPsw mouse. In contrast, the unconventional NSAID/antioxidant
curcumin was effective, lowering oxidative damage, cognitive
deficits, synaptic marker loss, and amyloid deposition. Curcumin
proved to be immunomodulatory, simultaneously inhibiting cytokine
and microglial activation indices related to neurotoxicity,
but increasing an index of phagocytosis. Curcumin directly targeted
Aß and was also effective in other models, warranting
further preclinical and clinical exploration.
