title: The role of neuroimmunomodulation in Alzheimer's disease.
abstract: The idea that alterations in the brain immunomodulation are critical for Alzheimer's disease (AD) pathogenesis provides the most integrative view on this cognitive disorder, considering that converging research lines have revealed the involvement of inflammatory processes in AD. We have proposed the damage signal hypothesis as a unifying scheme in that release of endogenous damage/alarm signals, in response to accumulated cell distress (dyslipidemia, vascular insults, head injury, oxidative stress, iron overload, folate deficiency), is the earliest triggering event in AD, leading to activation of innate immunity and the inflammatory cascade. Inflammatory cytokines play a dual role, either promoting neurodegeneration or neuroprotection. This equilibrium is shifted toward the neurodegenerative phenotype upon the action of several risk factors that trigger innate damage signals that activate microglia and the release of tumor necrosis factor-alpha, interleukin-6, and some trophic factors. In this neuroimmunomodulatory hypothesis we integrate different risk factors with microaglial activation and the resulting neuronal alterations and hyperphosphorylations of tau protein. The progression of AD, with slowly increasing damage in brain parenchyma preceding the onset of symptoms, suggests that tissue distress triggering damage signals drives neuroinflammation. These signals via toll-like receptors, receptors for highly glycosylated end products, or other glial receptors activate sensors of the native immune system, inducing the anomalous release of cytokines and promoting the neurodegenerative cascade, a hallmark of brain damage that correlates with cognitive decline.
authors.affiliation: International Center for Biomedicine, Faculty of Sciences, University of Chile, Santiago, Chile. rmaccion@manquehue.net
authors.forename: Ricardo B
authors.initials: RB
authors.lastname: Maccioni
authors.forename: Leonel E
authors.initials: LE
authors.lastname: Rojo
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Fernández
authors.forename: Rodrigo O
authors.initials: RO
authors.lastname: Kuljis
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D007107:Immune System / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D009420:Nervous System / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents