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 cognitive function. A progressive and irreversible brain disorder, AD is characterized by three major pathogenic episodes involving (a) an aberrant processing and deposition of beta -amyloid precursor protein (beta APP) to form neurotoxic beta-amyloid (betaA) peptides and an aggregated insoluble polymer of PA that forms the senile plaque, (b) the establishment of intraneuronal neuritic tau pathology yielding widespread deposits of agyrophilic neurofibrillary tangles (NFT) and (c) the initiation and proliferation of a brain-specific inflammatory response. These three seemingly disperse attributes of AD etiopathogenesis are linked by the fact that proinflammatory microglia, reactive astrocytes and their associated cytokines and chemokines are associated 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 processing with resultant overproduction of beta A42 and related neurotoxic peptides. Specific betaA fragments such as beta A42 can further potentiate proinflammatory mechanisms. Expression of the inducible oxidoreductase cyclooxygenase-2 and cytosolic phospholipase A(2) (cPLA(2)) are strongly activated during cerebral ischemia and trauma, epilepsy and AD, indicating the induction of proinflammatory gene pathways as a response to brain injury. Neurotoxic metals such as aluminum and zinc, both implicated in AD etiopathogenesis, and arachidonic acid, a major metabolite of brain cPLA(2) activity, each polymerize hyperphosphorylated tau to form NFT-like bundles. Further, epidemiological and longitudinal studies have identified a reduced risk for AD in patients (<70 yrs) previously treated with non-steroidal anti-inflammatory drugs for non-CNS afflictions that include arthritis. This review will focus on the interrelationships between the mechanisms of PS1, PS2 and <beta>APP gene expression, tau and betaA deposition and the induction, regulation and proliferation in AD of the neuroinflammatory response. Novel therapeutic interventions in AD are discussed.