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2012 Grants - Hoozemans
Age-Dependent Toll-Like Receptor Signalling in the Alzheimer's Brain
Jeroen Hoozemans, Ph.D.
VU University Medical Center Amsterdam
2012 New Investigator Research Grant
In the earliest stages of Alzheimer's disease, the protein fragment beta-amyloid tends to accumulate into toxic clumps within the brain. These clumps initiate a response from the body's immune system. Immune cells called microglia travel to sites where amyloid clumps have formed, and they have been shown to clear the protein fragment from the brain. Yet microglia may also become overactivated in the presence of beta-amyloid and induce brain inflammation. In an effort to explain this inflammation process, the researchers have found that proteins called toll-like receptors, which exist on the surface of microglia, appear to recognize and bind to beta-amyloid. It is unclear, however, how amyloid uses toll-like receptors to activate microglia.
In preliminary studies, Jeroen Hoozemans, Ph.D., and colleagues have used autopsied brain tissue from people with Alzheimer's disease to study toll-like receptor function. These tissue samples show increased activity of a protein called interleukin-1 receptor-associated kinase-4 (IRAK-4). The presence of IRAK-4 is necessary for toll-like receptors to initiate an immune system response to beta-amyloid. Yet if IRAK-4 activity becomes greater than normal, microglial function may become altered so that it promotes toxic inflammation. The researchers have found that by inhibiting IRAK-4 function, they could prevent microglia from releasing inflammation-inducing molecules called cytokines. Moreover, this procedure did not hinder microglia from carrying out the positive function of clearing beta-amyloid.
For their current study, Dr. Hoozemans and colleagues will further test the ability of IRAK-4 to prevent inflammation without hindering amyloid clearance. Using laboratory brain cells, they will search for mechanisms that underlie IRAK-4's role in human microglial activity. They will also test a related hypothesis, which says that brain inflammation increases with age in normal people and decreases with age in people that have Alzheimer's disease. For this experiment, the team will study brain tissue from people with and without Alzheimer's, comparing the presence of toll-like receptors, IRAK-4 protein and other markers of inflammation. Overall, the results of this effort could expand our understanding of how brain inflammation and dementia are linked.