Transgene: Crossbreeding of heterozygous human APP double mutant (PDAPP
with Swedish mutation) mouse and heterozygous human α-synuclein transgenic
Mutation: double mutations at KM670/671/NL (Swedish mutation) and V717F (Indiana
mutation); wild-type human α-synuclein
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.
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.
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.
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.
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