The role(s) of microglia in Alzheimer's disease remain unresolved. interactions of microglia with fibrillar beta amyloid peptides (fAbeta1-42) in vitro stimulates these cells to secrete H2O2, and pro-inflammatory cytokines. Anti-inflammatory drugs appear to exert an ameliorating effect on AD progression, and microgloial secretory products have been shown to be toxic to neurons. These observations suggest that microglia promote nerve damage and speed the progress of AD. Conversely, proteoglycans, block interactions of microglia with fAbeta in vitro, and coat fAbeta in vivo, thereby inhibiting microglial secretion of pro- inflammatory and neurotoxic substances, and suggesting that microglial-fAbeta interactions are relatively innocuous. Finally, treatment of transgenic mice expressing human amyloid precursor protein (Tg hAPP+/-) with anti-fAP IgG enables microglia to clear fAbeta-containing senile plaque-like structures from the brain, suggesting that microglia have the capacity to prevent and/or block progression of AD-like pathology. In preliminary experiments we have shown that microglial expression of surface receptors that mediate interactions with fAbeta is developmentally regulated, that scavenger receptors AI/II on adult microglia, and BI on astrocytes, bind fAP, that CD36 signals H2O2 secretion when microglia adhere to fAbeta-containing matrices, and that CD18 null microglia are incapable of secreting H2O2 when plated on these matrices. Using insights gained from these experiments, and Fcgamma receptor I/II/III-/- and CD18 null mice expressing Tg hAPP+/-, we will explore the roles of microglial in AD . The studies proposed have five specific aims: #1. Characterize differences in phenotype and gene expression patterns of newborn and adult mouse microglia treated with various growth factors, cytokines, and fAbeta-containing matrices. #2. Determine the roles) of p2-integrins in secretion and migration of mouse microglia and human macrophages on fAbeta- containing murices. #3. Determine the roles) of mouse microglial Fcgamma and complement receptors in uptake and degradation of fAbeta in vitro. #4. Assess effects of fAbeta-containing matrices, and of products secreted by wild type, CD18 null and Fcgamma receptor null microglia on neurons. #5. Determine the effects of fAbeta immunization of CD18 null -/Tg hAPP+/- and Fcgamma receptor null/Tg hAPP+/- mice on AD-like pathology.
| Wyss-Coray, Tony; Loike, John D; Brionne, Thomas C et al. (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9:453-7 |
| Husemann, Jens; Loike, John D; Anankov, Roman et al. (2002) Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40:195-205 |
