Alzheimer's disease (AD) is a progressive, neurodestructive process of the
human neocortex, characterized by the deterioration of memory and higher co
gnitive function. A progressive and irreversible brain disorder, AD is char
acterized by three major pathogenic episodes involving (a) an aberrant proc
essing and deposition of beta -amyloid precursor protein (beta APP) to form
neurotoxic beta-amyloid (betaA) peptides and an aggregated insoluble polym
er of PA that forms the senile plaque, (b) the establishment of intraneuron
al neuritic tau pathology yielding widespread deposits of agyrophilic neuro
fibrillary tangles (NFT) and (c) the initiation and proliferation of a brai
n-specific inflammatory response. These three seemingly disperse attributes
of AD etiopathogenesis are linked by the fact that proinflammatory microgl
ia, reactive astrocytes and their associated cytokines and chemokines are a
ssociated with the biology of the microtubule associated protein tau, betaA
speciation and aggregation. Missense mutations in the presenilin genes PS1
and PS2, implicated in early onset familial AD, cause abnormal beta APP pr
ocessing with resultant overproduction of beta A42 and related neurotoxic p
eptides. Specific betaA fragments such as beta A42 can further potentiate p
roinflammatory mechanisms. Expression of the inducible oxidoreductase cyclo
oxygenase-2 and cytosolic phospholipase A(2) (cPLA(2)) are strongly activat
ed during cerebral ischemia and trauma, epilepsy and AD, indicating the ind
uction of proinflammatory gene pathways as a response to brain injury. Neur
otoxic metals such as aluminum and zinc, both implicated in AD etiopathogen
esis, and arachidonic acid, a major metabolite of brain cPLA(2) activity, e
ach polymerize hyperphosphorylated tau to form NFT-like bundles. Further, e
pidemiological and longitudinal studies have identified a reduced risk for
AD in patients (<70 yrs) previously treated with non-steroidal anti-inflamm
atory drugs for non-CNS afflictions that include arthritis. This review wil
l focus on the interrelationships between the mechanisms of PS1, PS2 and <b
eta>APP gene expression, tau and betaA deposition and the induction, regula
tion and proliferation in AD of the neuroinflammatory response. Novel thera
peutic interventions in AD are discussed.