AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice

Abstract

Brain inflammation is a double-edged sword: it is required for brain repair in acute damage, whereas chronic inflammation and autoimmune disorders are neuropathogenic. Certain pro-inflammatory cytokines and chemokines are closely related to cognitive dysfunction and neurodegeneration. Representative anti-inflammatory cytokines, such as interleukin (IL)-10, can suppress neuroinflammation and have significant therapeutic potentials in ameliorating neurodegenerative disorders, such as Alzheimer’s disease (AD). Here, we show that adeno-associated virus (AAV) serotype 2/1 hybrid-mediated neuronal expression of the mouse IL-10 gene ameliorates cognitive dysfunction in APP+PS1 bigenic mice. AAV2/1 infection of hippocampal neurons resulted in sustained expression of IL-10 without its leakage into the blood, reduced astro/microgliosis, enhanced plasma amyloid-β peptide (Aβ) levels, and enhanced neurogenesis. Moreover, increased levels of IL-10 improved spatial learning as determined by the radial arm water maze. Finally, IL-10-stimulated microglia enhanced proliferation but not differentiation of primary neural stem cells in the co-culture system, while IL-10 itself had no effect. Our data suggest that IL-10 gene delivery has a therapeutic potential for a non-Aβ-targeted treatment of AD.

Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms

“…IL-10 expression mediated by adeno-associated virus (AAV) in the brains of AD animal models was reported to enhance neurogenesis and cognition [115]. Unexpectedly, further investigation opposed these findings, as AAV-mediated IL-10 expression increased the Ab burden and worsened cognitive impairment in AD animal models [116].…”

Interleukin-10 regulates progenitor differentiation and modulates neurogenesis on adult brain

“…Furthermore, little is known about the effects of anti-inflammatory cytokines on SVZ biology in health or in diseased states. In animal models of neurodegeneration, the administration of high doses of IL-10 as an anti-inflammatory agent improves functional parameters and progenitor proliferation (Kiyota et al, 2012;Yang et al, 2009). On the basis of our findings, we propose that increases in systemic IL-10 levels cause a downregulation of SVZ neurogenesis by directly delaying the normal activity of the neurogenic niche (summarized in Fig.…”

Alzheimer’s disease and cytokine IL-10 gene polymorphisms: is there an association?

“…This hypothesis is supported by studies, which described an increase of seven-to ten-fold in the production of IL-1β over IL-10 levels in AD patients when compared with control subjects 26 . 10 demonstrated that IL-10 significantly reduced neuroinflammation, enhanced neurogenesis and improved spatial cognitive dysfunction in transgenic AD mouse models. They showed that treatment with IL-10-adeno-associated virus of double-transgenic mice expressing familial AD mutants of amyloid precursor protein+presenilin-1 (APP+PS1 Tg), could suppress astro/microgliosis.…”

“…The associations between AD and inflammatory biomarkers, including the interleukins IL-1β, IL-2, IL-4, IL-6, IL-8, IL-12, IL-18, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and the C-reactive protein have been registered with controversial results 20 . However, interleukin-10 (IL-10), an anti-inflammatory mediator, has been pointed out as one of the main cytokines associated with the occurrence of AD 5,9,10 . Therefore, this study reviewed evidence of the role of IL-10 and its genetic polymorphisms in the context of AD.…”

“…In the last 15 years, a new theory has proposed the autoimmune mechanism as a trigger for AD. This theory involves a dysregulation of the blood-brain barrier, neurons, microglia, astrocytes and multiple cytokines 9, 10,11 . As reviewed by Naert and Rivest, activated microglia and astrocytes secrete inflammatory cytokines and chemokines, while age-related inflammation and chronic infection with herpes viruses might contribute to the systemic inflammation 12 .…”