Irizarry and collaborators (626.5) provided intriguing new results from transgenic mouse lines expressing human APP (the PDAPP mice) in the presence or absence of endogenous mouse ApoE. The PDAPP mice lacking ApoE have previously been reported to have diminished amyloid deposition (Nature Genetics 17:263) and no thioflavin S-positive plaques (indicating the absence of fibrillar amyloid deposits). The reduction in amyloid deposition in the cortex is striking but the focus of this presentation was on the pattern of amyloid staining in the hippocampal formation. In the PDAPP mice, amyloid is deposited as compact plaques distributed throughout the CA1 and CA3 regions of the hippocampus (mainly stratum radiatum and stratum oriens) and as a dense band of staining in the outer molecular layer of the dentate gyrus. In the absence of ApoE, however, a very different staining pattern is obtained. In these mice, the amyloid diffusely fills the CA1 and CA3 regions of the hippocampus but is almost absent in the dentate gyrus. In addition, the astrocytic response (increased GFAP staining) that is found around plaques in the PDAPP mice also seems to be less prominent and more diffuse in the ApoE-deficient line. This difference in distribution does not appear to be due to altered expression of the APP transgene, different levels of APP or Aβ, or to alterations in LRP protein or mRNA (a receptor that may serve to bind both ApoE and APP). In other words, there is no clear explanation for this effect. However, this striking alteration in amyloid deposition emphasizes the importance of the interaction between ApoE and amyloid in the dynamics of amyloid deposition. The transgenic mice are proving to be fruitful sources of new insights on the development of AD-like pathology.-Keith Crutcher.
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