mucke lab

Mutations in APP (and other proteins) that increase the production of APP-derived β-amyloid peptides (Aβ) cause autosomal dominant forms of AD. Interestingly, overexpression of such AD-mutant APPs in neurons of transgenic mice elicits AD-like changes in their brains. In collaboration with colleagues at UCSD and Elan Pharmaceuticals, we characterized the first transgenic mouse model to develop prominent AD-like pathology. In this model, the platelet-derived growth factor (PDGF) B chain promoter was used to direct high-level neuronal expression of an alternatively spliced minigene encoding AD-mutant forms of hAPP. This model shows high levels of cerebral Aβ expression and consistently develops striking AD-like CNS alterations, including typical amyloid plaques, astrocytosis, microgliosis, loss of presynaptic terminals, dystrophic neurites, as well as ultrastructural evidence for neuronal degeneration and intraneuronal Aβ aggregation. Subsequently, we used related constructs to generate a new set of PDGF-hAPP transgenic mice that express wild-type or FAD-mutant hAPPs at matching levels. This group of transgenic lines has made it possible to assess the relative roles of hAPP and Aβ in the development of AD-like pathologies in a manner that was previously impossible.

Since progress in this field had formerly been hampered by the inability of scientists to obtain high-expresser hAPP transgenic mice, it is worth noting in this context that we have distributed our PDGF-hAPP mice to various academic institutions, including Columbia University, Harvard University, Sun Health Research Institute, University of Kentucky, University of Paris, University of California at San Diego, University of Southern California, McGill University, Buck Institute, Rockefeller University, University of Z¸rich and Keio University.

Our studies in PDGF-hAPP mice revealed that amyloid plaque formation depended not only on the absolute levels of the highly fibrillogenic Aβ42 but also on the levels of the more soluble Aβ40. Mice with high levels of Aβ42 and a high Aβ42/Aβ40 ratio developed an abundance of plaques, whereas mice with similar levels of Aβ42 but higher levels of Aβ40 (lower Aβ42/Ab40 ratio) never developed plaques. These results suggest that Aβ40 may be antifibrillogenic in vivo. In contrast, astroglial expression of the human serine protease inhibitor a1-antichymotrypsin (ACT) strongly enhanced Aβ deposition in APP/ACT doubly transgenic mice. The cytokine transforming growth factor β1 (TGF-β1) had more complex effects on cerebral amyloid deposition, promoting cerebrovascular amyloidosis while inhibiting the formation of amyloid plaques in the brain parenchyma. These and related models are currently being used to develop and assess therapeutic strategies to prevent and reverse AD-like CNS alterations.