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Neuroinflammatory Signaling Upregulation in Alzheimer's Disease

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Abstract

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 β-amyloid precursor protein (βAPP) to form neurotoxic beta-amyloid (βA) peptides and an aggregated insoluble polymer of βA 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, βA speciation and aggregation. Missense mutations in the presenilin genes PS1 and PS2, implicated in early onset familial AD, cause abnormal βAPP processing with resultant overproduction of βA42 and related neurotoxic peptides. Specific βA fragments such as βA42 can further potentiate proinflammatory mechanisms. Expression of the inducible oxidoreductase cyclooxygenase-2 and cytosolic phospholipase A2 (cPLA2) 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 cPLA2 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 βAPP gene expression, tau and βA deposition and the induction, regulation and proliferation in AD of the neuroinflammatory response. Novel therapeutic interventions in AD are discussed.

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  1. Neuroscience Center and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA, 70112-2272

    Walter J. Lukiw & Nicolas G. Bazan

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Lukiw, W.J., Bazan, N.G. Neuroinflammatory Signaling Upregulation in Alzheimer's Disease. Neurochem Res 25, 1173–1184 (2000). https://doi.org/10.1023/A:1007627725251

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  • DOI: https://doi.org/10.1023/A:1007627725251

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