P1‐320: AAV‐mediated expression of anti‐inflammatory cytokines IL‐10 and IL‐4 significantly exacerbate amyloid pathology in the brains of APP TgCRND8 mice
Year: 2010
Type: article
Abstract: There have been conflicting reports of the involvement of the innate immune system and neuro-inflammation in the neuropathology of Alzheimer's disease (AD). Activated glial-induced neuro-inflammation following amyloid deposition has been purported to mediate cytotoxicity and neurodegeneration in AD. However, we have previously shown that Adeno Associated Viral (AAV) mediated expression of pro-inflammatory cytokines mIL-6, mIFNγ and TNFα in the brains of APP mice induced significant gliosis and concurrently attenuated Aβ deposition in vivo. These results suggest that upregulation of glial mediated phagocytosis and expression of other components of the innate immune system, e.g. complement system proteins, may help opsonize and remove Aβ deposits from the brain. In an effort to further characterize the role of the immune system and reactive gliosis in attenuating Aβ deposition, we have used (AAV) delivery techniques to express anti-inflammatory cytokines in the brains of APP transgenic mice. Our hypothesis was that dampening the extent of reactive gliosis will lead to increased plaque pathology. Using AAV serotype 1, we explored the effects of two murine anti-inflammatory cytokines, Interleukin 4 (IL-4) and Interleukin 10 (IL-10) in the brains of APP transgenic CRND8 mice. Expression of murine either IL-4 or IL-10 led to significantly increased amyloid deposition in APP CRND8 transgenic mice. IL-4 expression for 6 weeks in the hippocampus of adult AAP CRND8 mice led to ∼30% increase in amyloid deposition. IL-10 expression following PO injection (AAV transduction of the cerebral ventricles of neonatal APP CRND8 pups <12 hrs after birth) for 5 months led to ∼50% increase in amyloid deposition. We conclude that the increase in Aβ levels may be attributed to decreased glial phagocytic function. The function of anti inflammatory cytokines and resultant glial phenotypes in vivo and their potential role in affecting Aβ deposition will be further discussed. These results suggest that the context, timing and the compensatory effects of both pro-and anti-inflammatory cytokines play a critical role on the evolution of amyloid plaques in vivo.
Source: Alzheimer s & Dementia
Institutions: University of Florida, Mayo Clinic, Mayo Clinic in Florida
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1992234361