Todd Golde, M.D.

Modeling the Effects of "Modified" A beta Peptides on AD Pathogenesis

Using clues from the study of the BRI protein implicated in the pathogenesis of Familial British (FBD) and Danish (FDD) dementias, we have developed a novel system to selectively express individual Abeta peptides at high levels. This system has been used to generate transgenic mice that overexpress Abeta1-40 or Abeta1-42 at levels higher than the steady-state (pre-deposition) levels in APP transgenic mice. Additionally, adeno-associated virus (AAV) transduction of BRI-Abeta fusion proteins into the rat hippocampus indicates that viral transduction of these fusion constructs results in selective production of the expected Abeta peptide and that Abeta is expressed at much higher levels then can be achieved using AAV mediated transfer of an APP transgene. Collectively these experiments have demonstrated that overexpression of Abeta1-42, but not Abeta1-40, is sufficient to promote Abeta deposition in vivo and that BRI-Abeta fusion constructs are a more efficient way to deliver Abeta to the CNS then APP.

Herein, we propose to further explore the utility of AAV mediated transduction of BRI-Abeta fusion proteins to model certain aspects of AD pathogenesis in mice that are not likely to be modeled by any other method. We also propose to use this technology to deliver modified, potentially therapeutic, Abeta peptides to the CNS.