CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice.
Cytokines play an emerging role as neurotransmitters, neuromodulators, and neurohormones in the brain. This paradigm shift in cytokine function offers a new framework to understand their roles in ameliorating neurodegenerative disorders, such as Alzheimer's disease (AD). Molecular adjuvant therapy of AD animal models with glatiramer acetate induces anti-inflammatory responses and therapeutic effects. Although these effects are potentially mediated through anti-inflammatory cytokine signaling, the exact molecular identities and pathways are poorly understood. Here, we show that virus-mediated expression of the mouse interleukin (IL)-4 gene in beta-amyloid precursor protein + presenilin-1 (APP+PS1) bigenic mice attenuates AD pathogenesis. Introduction of an adeno-associated viral (AAV) vector encoding IL-4 into the hippocampus resulted in sustained expression of IL-4, reduced astro/microgliosis, amyloid-beta peptide (Abeta) oligomerization and deposition, and enhanced neurogenesis. Moreover, increased levels of IL-4 improved spatial learning, promoted phosphorylation of N-methyl-D-aspartate receptor subunit 2B at Tyr 1472, and enhanced its cell surface retention both in vivo and in vitro. Our data suggest that neuronal anti-inflammatory cytokine signaling may be a potential alternative target for non-Abeta-mediated treatment of AD.
Kiyota
Tomomi
T
Department of Pharmacology and Experimental Neuroscience, Nebraska Medical Center, Omaha, NE 68198, USA.
Okuyama
Satoshi
S
Swan
Russell J
RJ
Jacobsen
Michael T
MT
Gendelman
Howard E
HE
Ikezu
Tsuneya
T
D000544:Alzheimer Disease / Q000628:therapy*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D002490:Central Nervous System / Q000378:metabolism*; D015316:Genetic Therapy; D006624:Hippocampus / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics*; D015398:Signal Transduction; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D000893:Anti-Inflammatory Agents; D053764:Presenilin-1; D015847:Interleukin-4