Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation

Biochemical and genetic studies indicate that the inflammatory proteins, apolipoprotein E (ApoE) and alpha(1)-antichymotrypsin (ACT) are important in the pathogenesis of Alzheimer's disease (AD). Using several lines of multiply transgenic/knockout mice we show here that murine ApoE and human ACT separately and synergistically facilitate both diffuse Abeta immunoreactive and fibrillar amyloid deposition and thus also promote cognitive impairment in aged PDAPP(V717F) mice. The degree of cognitive impairment is highly correlated with the ApoE- and ACT-dependent hippocampal amyloid burden, with PDAPP mice lacking ApoE and ACT having little amyloid and little learning disability. A analysis of young mice before the onset of amyloid formation shows that steady-state levels of monomeric Abeta peptide are unchanged by ApoE or ACT. These data suggest that the process or product of amyloid formation is more critical than monomeric Abeta for the neurological decline in AD, and that the risk factors ApoE and ACT participate primarily in disease processes downstream of APP processing. (C) 2004 Elsevier Inc. All rights reserved.