General Information

Transgene: Crossbreeding of heterozygous human APP double mutant (PDAPP with Swedish mutation) mouse and heterozygous human α-synuclein transgenic mouse

Mutation: double mutations at KM670/671/NL (Swedish mutation) and V717F (Indiana mutation); wild-type human α-synuclein

Phenotype

Neuropathological Analysis:

Coexpression of human α-synuclein (hSYN) and human APP (hAPP) did not alter transgene expression, as indicated by similar levels of transgene derived hSYN and hAPP mRNAs in single or double transgenic littermates. Similarly, there was no effect at the protein level.

As they aged, all three transgenic mice--hSYN, hSYN, and hSYN/hAPP--lost significantly more cholinergic neurons in the nucleus basilis than did non-Tg mice (as measured by density of choline acetyltransferase-immunoreactivity at age 20-22 months). The greatest loss was in the hSYN/hAPP mice, which significantly more neurons even than the aging hAPP mice. In the caudate/putamen, only the aging hSYN/hAPP and hAPP mice lost more cholinergic neurons than control mice.

Concurrently, aging hAPP and hSYN/hAPP mice, but not hSYN mice, had a significant loss of synapses in the neocortex (as indicated by decreased synaptophysin immunoreactivity at age 20-22 months).

The accumulation of hSYN inclusions within neurons of singly transgenic mice (described in earlier research) was increased by 1.6-fold on average in the hSYN/hAPP mice. Electron microscopy indicated that whereas all inclusions in hSYN mice were amorphous, about 15% of inclusions in hSYN/hAPP mice were fibrillar, and contained A$, suggesting that A$ promotes the formation of Lewy-like bodies.

Behavioral analysis:

In rotorod testing at 6 months, hSYN/hAPP double transgenic mice, but not hSYN or hAPP single transgenic littermates, showed significant motor deficits relative to non-Tg littermate controls. By 12 months of age, both hSYN/hAPP and hSYN mice showed deficits compared to hAPP and control mice.

Conversely, in water maze tests of memory at 6 months of age, hSYN/hAPP and hAPP mice showed significant deficits relative to hSYN and control littermates.

Availability

Patents:

References

Primary:

Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L. $-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Nat Acad Sci U S A. 2001 Oct 9;98(21):12245-50.

Secondary:

Windisch M, Hutter-Paier B, Rockenstein E, Hashimoto M, Mallory M, Masliah E. Development of a new treatment for Alzheimer's disease and Parkinson's disease using anti-aggregatory beta-synuclein-derived peptides. J Mol Neurosci 2002 Aug-Oct;19(1-2):63-9. Abstract.

Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, Masliah E. Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 2002 Jun 1;68(5):568-78. Abstract .