There is growing interest in the overlap among Alzheimer's disease, Parkinson's disease, and less common synucleinopathies and tauopathies that can share features of both diseases. Two current papers looking at different levels of investigation-one focusing on molecular interactions between tau and α-synuclein (α-syn) proteins, and the other on clinical manifestations of AD and PD-add new information to this topic.
In tomorrow’s Science, Virginia Lee and her colleagues at the University of Pennsylvania in Philadelphia report that both tau and α-syn synergistically promote fibril formation by the other protein, which the authors hypothesize to be the seeds of pathological inclusions in some neurodegenerative diseases. Tau and α-syn proteins share some features, including the propensity to form pathogenic amyloid aggregates, and both co-occur in a number of diseases (see ARF meeting report on this subject).
When they incubated the two proteins together, Lee and colleagues found that α-syn, which readily polymerizes on its own, was able to induce polymerization of tau, which usually requires cofactors. There was also a reciprocal effect whereby tau induced greater polymerization of α-syn, especially at lower concentrations of α-syn. Although most fibrils were homopolymers of tau or α-syn, some were heteropolymers with tau at one end and α-syn at the other, suggesting that two homopolymers had joined.
In-vivo experiments accompanying these in-vitro data were that about 50 percent of mice transgenic for A53T mutant human α-syn had tau inclusions along with α-syn inclusions. In mice transgenic for both wild-type human α-syn and P301L mutant tau, the researchers found that α-syn and tau inclusions co-occurred in a subset of oligodendrocytes.
These results "suggest that therapeutic agents that directly or indirectly inhibit the formation of one form of amyloid might be effective on several of these neurodegenerative disorders," conclude the authors.
Research into common mechanisms for these neurodegenerative diseases has been driven in part by pathological overlaps between AD, PD, and related diseases, and by clinical observations that early parkinsonian signs may be harbingers of impending Alzheimer's disease. In this month’s Archives of Neurology, Robert Wilson and colleagues from the Rush Alzheimer's Disease Center in Chicago, Illinois, report on data from more than 700 Catholic clergy in the ongoing Religious Orders Study of aging and AD. These men had undergone annual clinical exams that included tests of cognitive function, clinical classification of AD, and a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). Over an average follow-up period of 4.6 years, the researchers found a relationship between parkinsonian progression (indicated by higher scores on the UPDRS) and increased risk of AD. Men in the highest tertile of UPDRS progression had an eightfold increased risk of developing AD relative to those without progression (P = .02). Similarly, the rate of decline on cognitive testing was correlated with increasing UPDRS scores. A potentially interesting new finding was that not all parkinsonian signs were associated with the increase in risk of AD or rate of cognitive decline-progression of gait disorder and rigidity were associated, but not bradykinesia or tremor.
The underlying reasons for this intersection of parkinsonian symptoms and AD are uncertain, say the authors. One possibility is that AD pathology in the substantia nigra is to blame. The authors mention that neurofibrillary tangles in the substantia nigra in AD have been associated with PD-like symptoms (Liu et al., 1997). Other factors mentioned include possible pathologic consequences of Lewy bodies or cerebrovascular disease.—Hakon Heimer
- Liu Y, Stern Y, Chun MR, Jacobs DM, Yau P, Goldman JE. Pathological correlates of extrapyramidal signs in Alzheimer's disease. Ann Neurol. 1997 Mar;41(3):368-74. PubMed.
- Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sørensen P. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol. 2003 Mar;60(3):387-92. PubMed.
- Wilson RS, Schneider JA, Bienias JL, Evans DA, Bennett DA. Parkinsonianlike signs and risk of incident Alzheimer disease in older persons. Arch Neurol. 2003 Apr;60(4):539-44. PubMed.
- Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003 Apr 25;300(5619):636-40. PubMed.