8 October 2001. A new double-transgenic mouse may provide a good model for Lewy-body
diseases and offer insight into mechanisms that underlie Alzheimer's and Parkinson's
disease. Eliezer Masliah and colleagues at University of California, San Diego, in La Jolla and UCSF in
San Francisco created the model by crossbreeding transgenic lines containing wild-type
human α-synuclein (hSYN) and mutant AβPP (hAβPP). The latter was previously
linked to familial Alzheimer's disease.
Parkinson's patients and 15-25 percent of Alzheimer's cases develop Lewy bodies,
intraneuronal structures containing α-synuclein.
In the Lewy-body variant of Alzheimer's disease, patients develop motor deficits
similar to Parkinson's disease and a more rapid cognitive decline. Conversely,
some Parkinson's patients develop dementia. These individuals have more severe
α-synuclein pathology and, often, amyloid plaques.
K et al).
These clinical findings suggest that there are distinct but overlapping pathways
in the two disorders involving an interaction between AbetaPP/A-β
and α-synuclein. Indeed, this possibility was proposed
by Masliah and his late colleague, Tsunao Saitoh, based on their discovery of
a fragment of α-synuclein in neuritic plaques.
The new mouse studies support this idea. In the double transgenics, mRNA levels
of hAβPP and hSYN in the brain were not altered relative to singly transgenic
littermates. At the protein level, AβPP was also unchanged, but synuclein
was elevated in the double transgenic. What's more, the number of synuclein
inclusions was increased 1.6-fold in the hAβPP/hSYN mice, and synuclein oligomers
and fibrils were seen in the hSYN/hAβPP mice, but not in the hSYN mice. These
results indicate that AβPP/A-β promotes the deposition of α-synuclein,
a speculation supported by in vitro studies.
Behavioral tests also indicate that AβPP and α-synuclein interact while
playing functionally distinct roles. hAβPP transgenic mice developed spatial
learning deficits but not motor deficits, while the reverse was true in hSYN
transgenics. The double transgenics displayed both types of deficits and in
more severe forms. Curiously, the motor deficit, which appeared by six months
in the double transgenic, did not progress, and by 12 months, both hSYN
and hSYN/hAβPP mice had similar deficits. The hSYN/hAβPP mice developed
a more pronounced learning deficit without any increase in plaque burden relative
to the hAPP single transgenics. These behavioral changes were mirrored by greater
reductions of cholinergic neurons and synaptophysin in the hSYN/hAβPP mice
than in the single transgenics.
What might be the mechanism(s) behind these effects? In a commentary
for the ARF, Ben Wolozin of Loyola University Medical Center in Maywood, Illinois,
observes that α-synuclein has only a "modest" tendency
to aggregate, and that its aggregation "is highly dependent on environmental
conditions." Masliah et al., speculate that Aβ42 and α-synuclein
may interact directly to enhance fibril formation, or that Aβ
may exert oxidative stress, leading to oxidative crosslinking of synuclein which
contributes to Lewy-body formation.
Drugs targeting Aβ formation or accumulation are
currently being developed for Alzheimer's disease, but these findings suggest
such therapies may apply to a variety of Lewy-body disorders. They may also
lead to novel drug targets. At a recent
workshop, Masliah presented data, in press in Neuron, showing that β-synuclein,
a homolog of α-synuclein, blocks α-synuclein
aggregation in vitro and in vivo in mice doubly transgenic for both α-
and β-synuclein. Thus β-synuclein
might pave the way to treatments for diseases involving α-synuclein
Masliah E et al. β-amyloid peptides enhance α-synuclein
accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's
disease and Parkinson's disease. Proc Natl Acad Sci U S A 2001 Oct 9;98(21):12245-50.