Anti-inflammatory regulation of beta-amyloidosis

DESCRIPTION (provided by applicant): The over-arching goal of this project is to determine the regulatory role of anti-inflammatory molecules on neuroinflammatory activities and beta-amyloidosis (A[unreadable] aggregation and deposition in brain) in rodent models of Alzheimer's disease (AD). Our previous studies on a double transgenic mouse expressing familial AD mutants of [unreadable]-amyloid precursor protein (APP) and glial fibrillar acidic protein promoter-driven murine CCL2 and APP transgenic mice lacking interferon-? receptor type I demonstrated that chemokines and pro-inflammatory cytokines are critically involved in progression of beta-amyloidosis and microgliosis in brain. Accordingly, glatiramer acetate immunization, a known anti-inflammatory therapy, reduced beta-amyloidosis, enhanced neurogenesis, and improved cognitive function in APP mice. In addition, specific anti-inflammatory cytokines (interleukin-4;IL-4, IL-10, among others) can directly induce anti-inflammatory and neuroprotective phenotype of microglia. Thus, we hypothesize that anti-inflammatory cytokines (IL-4 or IL-10, among others) may induce suppression of neuroinflammation and beta-amyloidosis-related cognitive dysfunction in vivo. Our preliminary studies support this hypothesis, since chronic expression of neutralizing CCL2 mutant (7ND, lacking the first 7 amino acid sequence) suppresses microgliosis and A[unreadable] oligomer accumulation, and improves cognitive function in a double transgenic mice (APP/PS1) expressing APP and presenilin-1 (PS1). Using adeno-associated virus (AAV)-mediated gene delivery system for expressing IL-4, IL-10, 7ND in APP/PS1 mice at pre- and post- symptomatic stages of memory dysfunction, we will ask the following questions: 1) Does 7ND, IL-4, or IL-10 suppress astro/microgliosis? If so, is it restricted to hippocampal region or both in cortex and hippocampus?;2) Does IL-4 or IL-10 induce dendritic-like (CD11c+) microglia? If so, is it neuroprotective?;3) Does IL-4 or IL- 10 induce inflammation regulatory molecules (CD200, CD200R)?;4) Does IL-4 or IL-10 reduce beta- amyloidosis? If so, is it specific to compact plaques, diffuse plaques, or A[unreadable] oligomers?;5) Does IL-4 or IL-10 enhance neurogenesis? If so, is it accompanied with enhanced newly synthesized neurons or astrocytes? 6) Does IL-4 or IL-10 enhance synaptogenesis? If so, is it specific to presynaptic or postsynaptic molecules?;and 7) Does 7ND, IL-4 or IL-10 enhance memory formation after injection of lower doses of AAV? If so, is it effective in both pre-symptomatic and post-symptomatic stages? This proposal is significant, since to the best of our knowledge, therapeutic efficacy of 7ND, IL-4 or IL-10 gene delivery has never been tested in APP or APP/PS1 mice in vivo. These approaches may have significant implication for immunotherapy of AD and other neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a leading neurological disease that affects more than 4 million people in the US, who are left without effective therapy. Using the established the genetically engineered mouse model of AD (APP/PS1 mice), we will characterize the beneficial effect of anti-inflammatory cytokines (interleukin-4 and 10) and neutralizing chemokine mutant (for CCL2), on beta-amyloidosis and cognitive function inAPP/PS1 mice. These approaches may have therapeutic implication for AD and other neurodegenerative diseases.