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P2‐327: Inflammation‐induced inhibition of brain‐to‐blood efflux of amyloid beta is independent of LRP‐1 expression and reversed by the antioxidant N‐acetylcysteine
Author(s) -
Erickson Michelle,
Banks William
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1203
Subject(s) - acetylcysteine , efflux , oxidative stress , blood–brain barrier , inflammation , pharmacology , lipopolysaccharide , amyloid beta , endocrinology , medicine , chemistry , antioxidant , central nervous system , biochemistry , disease
pathological species;OR,3) a combination of these two, dependingon the spatio-temporal context and levels of expression of different inflammatory mediators.Methods: Using rAAVmediated gene delivery, we have achieved high levels of expression of different cytokines in Alzheimer mice brains. Bymodulating the extent of gene expression invivo, this technique allows us to test the long-term effect of potential neurotoxic inflammatory mediators in the CNS. This also bypasses the often confounding problems inherent in creating bitransgenic mice and permits us to dissect the role of individual innate immune mediators in development of Alzheimer pathology rapidly and in a cost-effective manner.Results: In an effort to characterize the role of innate inflammatory mediators on amyloid beta (Abeta) pathology and tau pathology in vivo, we overexpressed several mouse cytokines, namely, Interleukin-6, Interferongamma,TumorNecrosisFactor-alpha, Interleukin-1beta, Interleukin-4 and Interleukin-10 in mice brains using adeno associated virus (AAV2/1) mediated gene delivery. Here, we present a comprehensive review of our data on the effect of these cytokines on1)Abeta pathology inKM670/671/NL+V717Fmutant Amyloid precursor protein transgenic TGCRND8 mice and 2) tau pathology in P301L tau transgenic JNPL3 mice. Extensive analysis shows that pro-inflammatory cytokine mediated reactive gliosis may be beneficial early in the disease process by potentially enhancing Abeta plaque clearance rather thanmediating a neurotoxic feedback loop that exacerbates amyloid pathology. Additionally, expression of anti-inflammatory cytokines exacerbated Abeta plaque pathology, indicating that suppression of glial activation may have detrimental effects onAlzheimer pathology inAPP transgenicmice. Further functional assessment of these innate immune mediators on Alzheimer like tau pathology will be discussed.Conclusions: Our data raises an intriguing possibility that engagement of the innate immune system early on during disease pathogenesis may contribute to attenuation of Alzheimer like pathology in preclinical mouse models.