9 November 2005. If the amyloid hypothesis can explain Alzheimer disease (AD), can it also explain why some people with AD develop Parkinson-like symptoms? A paper in the current Journal of Neuroscience reports that in mice, the amyloid-β peptide (Aβ) can cause dysfunction in extrapyramidal neurons in the striatum and the substantia nigra, two regions hard hit in Parkinson disease (PD).
According to some estimates, 35-40 percent of AD patients develop a type of Parkinsonism (see, for example, Scarmeas et al., 2004. In fact, John Trojanowksi and colleagues reported that many people with familial AD (caused by presenilin or Aβ precursor protein mutations) develop Lewy bodies (LB), dense intraneuronal inclusions that are a key feature of Parkinson disease (see Lippa et al., 1998). These findings suggest that overproduction of Aβ is sufficient to precipitate LBs and cause Parkinsonism in the Lewy body variant of AD. Now, using transgenic mice expressing human familial AD mutations (APP Swedish and presenilin 1 δE9) Elliott Mufson and colleagues at Rush University Medical Center, Chicago, link striatal deposition of Aβ to nigrostriatal dysfunction.
First author Sylvia Perez and colleagues reported at the Society for Neuroscience meeting last year that these double transgenic mice have morphological alterations and Aβ deposition. Now, Perez and colleagues extend those observations, correlating Aβ accumulation with dysfunctional dopaminergic striatal neurons. Using immunohistochemical methods, the authors found that Aβ deposits occur in the striatum as early as 4 months old. By 6 months they are readily detected, and by 15-17 months they coincide with dystrophic neurites testing positive for tyrosine hydroxylase, a marker of dopaminergic neurons.
Though the number of dopaminergic neurons appears to remain stable over the lifespan of these animals, Perez and colleagues found that the expression of tyrosine hydroxylase (TH) changed. By 10-12 months, TH levels in substantia nigra of the double transgenics were almost twice those in 3-6-month-old animals. In addition, levels of the dopamine metabolite DOPAC (3,4-dihydroxyphenylacetic acid) were found to fluctuate. Compared to age-matched wild-type animals, 3-6-month-old transgenic animals had slightly, though significantly elevated DOPAC. But by the time the animals were 10-12 months old, DOPAC levels had fallen back to normal.
All told, the authors interpret the data to suggest that Aβ may play a critical role in promoting striatal dopaminergic dystrophic neurites, leading to dopaminergic dysfunction in the basal ganglia. It would be interesting to see if these mice develop Lewy body-like inclusion bodies, as do mice that express mutant human APP and wild-type human α-synuclein, a major LB component (see ARF related news story). “It is possible that β amyloid is involved in protein aggregation that leads to various types of inclusions, including Lewy bodies in PD and AD/PD,” said Mufson.
Moreover, it would also be interesting to test these animals for changes in monoamine oxidase, the enzyme that de-aminates dopamine to yield DOPAC. “It is possible that MAO or mitochondrial dysfunction are factors underlying striatal DOPAC changes in APPswe/PS1δE9 tg mice,” the authors suggest in the paper. MAO resides on the outer membrane of the mitochondria, which have been implicated in numerous ways with Parkinson disease pathology (see ARF related news story, ARF news story, and ARF news story).—Tom Fagan.
Perez SE, Lazarov O, Koprich JB, Chen E-Y, Rodriguez-Mendez V, Lipton JW, Sisodia SS, Mufson EJ. Nigrostriatal dysfunction in familial Alzheimer’s disease-linked APPswe/PS1deltaE9 transgenic mice. J. Neurosci. November 2, 2005;25:10220-10229. Abstract