Neuroimmunomodulation in the pathogenesis of Alzheimer's disease.
Evidence has been cumulated on the role of microglia cells deregulation and alterations in their interaction patterns with brain neurons, in the pathway towards neurodegeneration in Alzheimer's disease (AD). After the failure of the amyloid hypothesis to explain AD pathogenesis, current hypotheses focus on tau self-polymerization into pathological oligomers and filaments as a major culprit for neurofibrillary degeneration. It is worth pointing out that formation of tau polymers is consistent with the clinical and neuropathological observations, and that tangles are pathognomonic of AD and related tau disorders. In this context, inflammatory processes play a major role in neuronal degeneration. On the basis of studies on microglia and neuronal cultures, together with experiments in animal models, and the clinical evidence, we postulated that a series of endogenous damage signals activate microglia cells, inducing NFkappa-beta with the consequent release of cytokine mediators such as TNF-alpha, IL-6 and IL-1beta. An overexpression of these mediators may trigger signaling cascades in neurons leading to activation of protein kinases gsk3beta, cdk5, abl kinases, along with inactivation of phosphatases such as PP1, with the resulting hyperphosphorylation and self-aggregation of tau protein into neurotoxic oligomeric species.
Morales
Inelia
I
Laboratory of Cellular and Molecular Neurosciences (LCMN), Faculty of Sciences and International Center for Biomedicine (ICC), Nuñoa Santiago, Chile.
Farías
Gonzalo
G
Maccioni
Ricardo B
RB
D000544:Alzheimer Disease / Q000276:immunology* / Q000503:physiopathology; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004660:Encephalitis / Q000276:immunology* / Q000503:physiopathology; D005911:Gliosis / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D017628:Microglia / Q000276:immunology*; D009410:Nerve Degeneration / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D015213:Neuroimmunomodulation / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4