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. (Ueda 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 deposition.—June Kinoshita
- Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11282-6. PubMed.
- Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L. beta-amyloid peptides enhance alpha-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. PubMed.