Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease.
Alzheimer's disease (AD) is the most common neurodegenerative disorder that affects the elderly. The increase of life-expectancy is transforming AD into a major health-care problem. AD is characterized by a progressive impairment of memory and other cognitive skills leading to dementia. The major pathogenic factor associated to AD seems to be amyloid-beta peptide (Aβ) oligomers that tend to accumulate extracellularly as amyloid deposits and are associated with reactive microglia and astrocytes as well as with degeneration of neuronal processes. The involvement of microglia and astrocytes in the onset and progress of neurodegenerative process in AD is becoming increasingly recognized, albeit it is commonly accepted that neuroinflammation and oxidative stress can have both detrimental and beneficial influences on the neural tissue. However, little is known about the interplay of microglia, astrocytes and neurons in response to Aβ, especially in the early phases of AD. This review discusses current knowledge about the involvement of neuroinflammation in AD pathogenesis, focusing on phenotypic and functional responses of microglia, astrocytes and neurons in this process. The abnormal production by glia cells of pro-inflammatory cytokines, chemokines and the complement system, as well as reactive oxygen and nitrogen species, can disrupt nerve terminals activity causing dysfunction and loss of synapses, which correlates with memory decline; these are phenomena preceding the neuronal death associated with late stages of AD. Thus, therapeutic strategies directed at controlling the activation of microglia and astrocytes and the excessive production of pro-inflammatory and pro-oxidant factors may be valuable to control neurodegeneration in dementia.
Agostinho
Paula
P
Center for Neurosciences of Coimbra, Faculty of Medicine - Pólo I (1st floor), Rua Larga, University of Coimbra, 3004-504 Coimbra, Portugal. pagost@cnc.cj.uc.pt
Cunha
Rodrigo A
RA
Oliveira
Catarina
C
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000276:immunology
D000975:Antioxidants; D018836:Inflammation Mediators