Neuroinflammatory signaling upregulation in Alzheimer's disease

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.