Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease

In Alzheimer disease (AD), neurons are thought to be subjected to the deleterious cytotoxic effects of activated microglia. We demonstrate that binding of amyloid-beta peptide (A[Beta]) to neuronal Receptor for Advanced Glycation Endproduct (RAGE), a cell surface receptor for A[Beta], induces macrophage-colony stimulating factor (M-CSF) by an oxidant sensitive, nuclear factor [Kappa]B-dependent pathway. AD brain shows increased neuronal expression of M-CSF in proximity to A[Beta] deposits, and in cerebrospinal fluid from AD patients there was [approximately equal to]5-fold increased M-CSF antigen (P < 0.01), compared with age-matched controls. M-CSF released by A[Beta]-stimulated neurons interacts with its cognate receptor, c-fms, on microglia, thereby triggering chemotaxis, cell proliferation, increased expression of the macrophage scavenger receptor and apolipoprotein E, and enhanced survival of microglia exposed to A[Beta], consistent with pathologic findings in AD. These data delineate an inflammatory pathway triggered by engagement of A[Beta] on neuronal RAGE. We suggest that M-CSF, thus generated, contributes to the pathogenesis of AD, and that M-CSF in cerebrospinal fluid might provide a means for monitoring neuronal perturbation at an early stage in AD.