Claims
- 1. A transgenic mouse comprising:
a first transgenic nucleotide sequence, integrated into the genome of said mouse, encoding human amyloid precursor protein (hAPP) operably linked to a first promoter; and a second transgenic nucleotide sequence, integrated into the genome of said mouse, encoding human (h) α-synuclein operably linked to a second promoter; wherein the first and second transgenic nucleotide sequences are expressed, and wherein, as a result of said expression, said transgenic mouse develops neurodegenerative disease.
- 2. The transgenic mouse of claim 1, wherein said first promoter comprises a platelet-derived growth factor β (PDGF-β) promoter.
- 3. The transgenic mouse of claim 2, wherein a simian virus (SV)40 derived intron operably links said PDGF-β promoter to said first transgenic nucleotide sequence.
- 4. The transgenic mouse of claim 1, wherein said first promoter comprises a Thy1 promoter.
- 5. The transgenic mouse of claim 1, wherein said first promoter comprises a prion (PrP) promoter.
- 6. The transgenic mouse of claim 1, wherein said first promoter comprises a PDGF-β promoter.
- 7. The transgenic mouse of claim 6, wherein a SV40 derived intron operably links said PDGF-β promoter to said second transgenic nucleotide sequence.
- 8. The transgenic mouse of claim 1, wherein said second promoter comprises a Thy1 promoter.
- 9. The transgenic mouse of claim 1, wherein said second promoter comprises a PrP promoter.
- 10. The transgenic mouse of claim 1, wherein said second promoter comprises a PDGF-β promoter.
- 11. The transgenic mouse of claim 10, wherein a SV40 derived intron operably links said PDGF-β promoter to said second transgenic nucleotide sequence.
- 12. The transgenic mouse of claim 1, wherein proteins encoded by the first and second transgenic nucleotide sequences are overexpressed as compared to a non-transgenic mouse of the same strain.
- 13. The transgenic mouse of claim 1, wherein the nucleotide sequence of hAPP comprises introns between exons 6 through 9 of hAPP.
- 14. The transgenic mouse of claim 1, wherein the nucleotide sequence encoding hAPP encodes hAPP770.
- 15. The transgenic mouse of claim 1, wherein the nucleotide sequence encoding hAPP encodes hAPP751.
- 16. The transgenic mouse of claim 1, wherein the nucleotide sequence encoding hAPP encodes hAPP695.
- 17. The transgenic mouse of claim 1, wherein the hAPP is a mutant hAPP.
- 18. The transgenic mouse of claim 17, wherein the nucleotide sequence encoding the mutant hAPP encodes a protein that contains a change from lysine to asparagine at amino acid 670 and a change from methionine to leucine at amino acid 671.
- 19. The transgenic mouse of claim 17, wherein the nucleotide sequence encoding the mutant hAPP encodes a protein that contains a change from valine to isoleucine at amino acid 717.
- 20. The transgenic mouse of claim 17, wherein the nucleotide sequence encoding the mutant hAPP encodes a protein that contains a change from valine to phenylalanine at amino acid 717.
- 21. The transgenic mouse of claim 1, wherein the nucleotide sequence encoding hAPP encodes only a portion of hAPP.
- 22. The transgenic mouse of claim 21, wherein hAPP is Aβ1-42.
- 23. The transgenic mouse of claim 1, wherein the nucleotide sequence of α-synuclein comprises a coding sequence of α-synuclein.
- 24. The transgenic mouse of claim 1, wherein the hα-synuclein is a mutant hα-synuclein.
- 25. The transgenic mouse of claim 24, wherein the nucleotide sequence encoding the mutant hα-synuclein encodes a protein that contains a change from alanine to proline at amino acid 30.
- 26. The transgenic mouse of claim 24, wherein the nucleotide sequence encoding the mutant hα-synuclein encodes a protein that contains a change from alanine to threonine at amino acid 53.
- 27. A transgenic mouse comprising:
a first transgenic nucleotide sequence, integrated into the genome of said mouse, encoding human amyloid precursor protein (hAPP) operably linked to a platelet derived growth factor β (PDGF-β) promotor operably linked to a simian virus (SV)40 intron; a second transgenic nucleotide sequence, integrated into the genome of said mouse, encoding human (h) α-synuclein operably linked to a PDGF-β promoter operably linked to an SV40 intron; wherein the first and second transgenic nucleotide sequences are expressed, and wherein, as a result of said expression, said transgenic mouse develops neurodegenerative disease.
- 28. The transgenic mouse of claim 27, wherein proteins encoded by the first and second transgenic nucleotide sequences are overexpressed as compared to a non-transgenic mouse of the same strain.
- 29. The transgenic mouse of claim 27, wherein the hAPP comprises a coding sequence containing introns between exons 6 through 9.
- 30. The transgenic mouse of claim 27, wherein the hAPP contains a mutation of valine to isoleucine at amino acid 717.
- 31. The transgenic mouse of claim 27, wherein hα-synuclein comprises the coding sequence of hα-synuclein.
- 32. The transgenic mouse of claim 27, wherein neurodegenerative disease comprises formation of intraneuronal inclusions characteristic of Lewy body disease.
- 33. The transgenic mouse of claim 27, wherein neurodegenerative disease comprises formation of fibrillary Lewy body-like inclusions.
- 34. The transgenic mouse of claim 27, wherein neurodegenerative disease comprises neuronal death.
- 35. The transgenic mouse of claim 27, wherein neurodegenerative disease comprises development of motor deficits.
- 36. The transgenic mouse of claim 27, wherein age of onset of neurodegenerative disease occurs at a significantly (p<0.05) younger age than in singly transgenic littermates.
- 37. A method for screening therapeutic agents for the prevention or treatment of neurological disease comprising administration of therapeutic interventions to a transgenic mouse comprising:
a first transgenic nucleotide sequence, integrated into the genome of said mouse, encoding human amyloid precursor protein (hAPP) operably linked to a first promoter; a second transgenic nucleotide sequence, integrated into the genome of said mouse, encoding human (h) α-synuclein operably linked to a second promoter; wherein the first and second transgenic nucleotide sequences are expressed, and wherein, as a result of said expression, said transgenic mouse develops neurodegenerative disease.
GOVERNMENT INTEREST
[0001] The invention was made with government support from the National Institutes of Health under grant number AG10869.