A new mouse model of combined Aβ and tau pathology reveals that the pair deliver a one-two punch to mitochondria. The work, from Anne Eckert and colleagues at the University of Basel in Switzerland, along with Jürgen Götz at the University of Sydney, Australia, indicates that the two pathologies work at different sites to decrease energy production in cortical neurons. The work, published November 6 in PNAS online, establishes a molecular link between Aβ and tau and further implicates mitochondrial malfunction in Alzheimer disease pathology.
The triple-transgenic mice are the offspring of a new double-transgenic line bearing the human presenilin 2 gene N141I and amyloid precursor protein Swedish mutant genes (recently made at Hoffmann-La-Roche AG in Basel; see Ozmen et al., 2009) cross-bred with Götz’s TauP301L mouse (Götz et al., 2001). The production and characterization of the triples was recently published (Grueninger et al., 2009). The new mice are only the second model of mixed pathology to be developed, after the triple transgenic (3xTgAD) made in Frank LaFerla’s lab at the University of California, Irvine (Oddo et al., 2003). Compared to the 3xTgAD model, the new mice develop tau pathology earlier, a trait of the parental tau transgenic pR5 strain that shows neurofibrillary tangle formation in the amygdala at around five to six months of age.
First author Virginie Rhein and colleagues performed a proteomic analysis of crude synaptosomal or “vesicular” fractions from the mice, comparing wild-type, the parental strains that had only Aβ or tau, and the triple transgenics. The researchers chose these preparations because they contain synaptic proteins and mitochondria, two targets of AD pathology. They used peptide labeling, chromatography and mass spectrometry to identify and quantitate proteins in each sample. Of 1,275 proteins quantified, 24 were significantly increased or decreased in the triple transgenic mice compared to wild-type, APP/PS or tau mice. Of these, one-third were mitochondrial proteins.
That result prompted the researchers to examine oxidative phosphorylation in isolated mitochondria from the four mouse strains. Previous work had shown that tau-only mice developed deficiency in the activity of complex I, the first step in the electron transport chain, by eight months of age (David et al., 2005). The new data showed that eight-month-old APP/PS and the triple transgenic mice developed cortex-specific deficiencies in oxidative phosphorylation. At this age, only the triple transgenic line showed loss of membrane potential, suggesting that the Aβ and tau pathologies together were more damaging to mitochondrial function. This could be because tau and Aβ act at different points in the electron transport chain; both the proteomic analysis and activity measures pointed to complex I as the site of tau action, while Aβ affected complex IV and promoted general uncoupling.
The results suggest that the synergistic effects of Aβ and tau may play out at least in part at the level of the mitochondria. Götz and colleagues have shown previously that mitochondria from the tau mice are more sensitive to Aβ toxicity in vitro (Eckert et al., 2008). One explanation is that tau’s inhibition of complex I renders mitochondria more susceptible to the effects of Aβ. Consistent with this idea, the researchers observed an upregulation of complex I activity in eight-month-old APP-transgenic mice, which they speculate represents an attempt to compensate for disruption in other parts of the chain. However, with time, those compensatory mechanisms fail, and mitochondrial function degrades. In the presence of mutant transgenic tau, the failure happens earlier, the authors show. The result is that by 12 months, the triple transgenics showed a 50 percent reduction in cortical ATP levels and a 25 percent increase in superoxide anions and reactive oxygen species compared to wild-type mice.
The newly bred triples offer an advantage over the previously studied 3xTgAD mice, says Götz, because they allow researchers to analyze the actions of Aβ and tau individually. “We have a long-standing interest in synergistic effects of Aβ and tau. To be able to discriminate effects that are due to only Aβ or tau from effects that are due to both triggers simultaneously, we had to use mice that develop either tangles or plaques or both. This comparative analysis is not possible in the 3xTgAD model, as the two transgenes in that case have been co-injected and hence, co-integrated,” he wrote in an e-mail to ARF.
“With regards to mitochondrial function, 3xTgAD mice have, as far as I understand, not been investigated as extensively as this has been done for our PNAS publication. Our study allows us to conclude that while Aβ and tau act synergistically on mitochondria, deregulation of mitochondrial complex I is tau-dependent, and deregulation of complex IV is Aβ-dependent, both at the protein and activity levels,” Götz wrote. Mitochondrial problems have been reported in the triple transgenics, starting as early as embryonic development (see ARF related news story on Yao et al., 2009), but the relative contributions of the different transgenes was not clear.
Co-author Christian Czech, a scientist at Hoffman-La-Roche where the mice were produced, wrote to ARF, “We generated this TauPS2APP mouse model with the aim to identify a direct link between amyloid pathology, tau pathology, and, eventually, neurodegenerative processes. This mouse model will be very useful for assessing therapeutic interventions addressing amyloidosis and/or tau pathology.” The company made the mice available to Eckert and Götz for their studies, and the mice are “in principle” available to other researchers under a materials transfer agreement, Czech told ARF.—Pat McCaffrey
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- Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, Ozmen L, Bluethmann H, Dröse S, Brandt U, Savaskan E, Czech C, Götz J, Eckert A. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20057-62. PubMed.