This application describes a new transgenic mouse model for the study of Abeta amyloid deposition in brain, and the pathological consequences of amyloid deposition. These mice derive from a cross between Tg2576, a line expressing a mutant form of the human amyloid precursor protein gene (APP), and M146L5.1, a line expressing a mutant form of the human presenilin-1 gene (PS1). Like other transgenic lines overexpressing APP, these mice do not exhibit detectable neurodegeneration, nor is the inflammatory reaction in these mice similar to that found in Alzheimer's disease (AD) brain. In this manner the transgenic mice resemble the 5 percent of nondemented elderly individuals who exhibit substantial Abeta amyloid plaque pathology at autopsy (referred to as high plaque normals or high pathology controls). One surprising feature of mouse immunity is a relative lack of complement activity compared to other species (including humans). Increasing evidence suggests that the reaction between fibrillar Abeta and complement (specifically component C1q) integrally participates in an inflammatory cascade cycle that ultimately leads to bystander effects on neural tissue. The hypothesis tested in this proposal is that low levels of complement activation by Abeta, either due to insufficient quantities of complement, or qualitative differences in the structure of human and murine complement, limits the extent of the AD phenotype expressed by the transgenic mice. To test this hypothesis, doubly transgenic mice will a) be bred into a mouse strain that has relatively high levels of complement activity, b) the innate immune system will be directly activated with LPS or IL-1 infusions or c) supplemented with human C1q. The degree to which these manipulations enhance the manifestation of the AD phenotype will be evaluated by immunocytochemistry and immunoassay.
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