The senile plaque is a pathological hallmark of Alzheimer's disease (AD). It is composed of beta amyloid fibrils (fAbeta), activated microglia, astrocytes and degenerating neurons. Data from patients and animal models of AD indicate that accumulation of microglia in senile plaques contributes significantly to neuronal degeneration. A key step is the migration of microglia to sites of fAbeta deposition. A likely course of events includes: (1) local microglia and astrocytes bind to fAbeta deposited in their vicinity, (2) this induces them to produce chemoattractants that recruit additional microglia, (3) recruited microglia adhere to fAbeta, become activated to produce neurotoxins, and other inflammatory mediators that cause neuronal damage. (4) Activated microglia are then retained in the senile plaques and continue to produce neurotoxins. We propose to investigate the mechanism of recruitment, activation and retention of microglia in senile plaques in AD. For this purpose we will use: (a) an in vitro model for microglial and astrocyte interactions with fAbeta, (b) post-mortem human brain specimen of patients with AD, and (c) transgenic APP mice (Tg2576) that develop AD-like pathology. We propose three specific aims:
Aim 1. Identify chemoattractants produced by microglia and astrocytes interacting with fAbeta and determine their mechanism of production. We have preliminary data indicating that two chemokines, MCP-1 and fractalkine, can mediate migration of microglia to sites of fAbeta deposition in vitro.
Aim 2. Study the effect of MCP-1, fractalkine and other chemoattractants; identified in aim 1 on key microglial functions important in the pathogenesis of AD. We will determine the role(s) of these chemokines in fAbeta-mediated activation of microglia to produce neurotoxins, and in microglial retention at sites of fAbeta deposition.
Aim 3. Analyze the effect of targeted disruption or upregulation of MCP-1, CCR2, fractalkine or CX3CR1 on AD-like pathology in transgenic APP mice Tg2576. We will cross breed mice with targeted disruption or up-regulation of MCP-1, CCR2, and fractalkine genes with transgenic APP mice Tg2576 and test the resultant double transgenic mice for markers of AD. Chemokines and their receptors are attractive therapeutic targets in many inflammatory processes. Understanding the role of chemokines in recruitment and activation of microglia in AD may lead to exciting novel therapeutic targets to delay or stop the progression of AD by delaying or inhibiting the accumulation or activation of microglia at sites of deposition.
| Medeiros, Lea A; Khan, Tayeba; El Khoury, Joseph B et al. (2004) Fibrillar amyloid protein present in atheroma activates CD36 signal transduction. J Biol Chem 279:10643-8 |
| El Khoury, Joseph B; Moore, Kathryn J; Means, Terry K et al. (2003) CD36 mediates the innate host response to beta-amyloid. J Exp Med 197:1657-66 |
| Moore, Kathryn J; El Khoury, Joseph; Medeiros, Lea A et al. (2002) A CD36-initiated signaling cascade mediates inflammatory effects of beta-amyloid. J Biol Chem 277:47373-9 |
| Coraci, Indra Sethy; Husemann, Jens; Berman, Joan W et al. (2002) CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 160:101-12 |
