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.

Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, Ozmen L, Bluethmann H, Drose S, Brandt U, Savaskan E, Czech C, Gotz J, Eckert A. Amyloid-b and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. PNAS Early Edition. 2009 Nov 6. Abstract


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  1. Mitochondria have been implicated in Alzheimer disease for several years; however, whether they are causally involved in the pathogenesis of this neurodegenerative disorder is still a matter of debate. Eckert and coworkers publish now a study proposing a molecular link between Aβ and tau protein via mitochondria in AD pathology in vivo. The authors have elegantly established a correlation between AD-like symptoms in their mouse model with mitochondria dysfunction, as shown by deficits at the level of the mitochondria membrane potential and at the level of the electron transport chain, as well as with increasing oxidative stress.

    A possible mode of action of tau mutant protein upon mitochondria has been suggested by Stoothoff and colleagues. They have shown that mitochondrial transport along the axons is disturbed in the presence of isoform 3 and 4 of tau (Stoothoff et al., 2009). Additionally, it is thought that the hyperphosphorylated form of tau causes toxicity in AD brain. Some reports suggest that reduced mitochondrial energy levels cause hyperphosphorylation and consequent aggregation of tau (Swerdlow and Khan, 2004; Escobar-Khondiker et al., 2007). These studies, along with many others, support a “mitochondrial cascade hypothesis” for AD.

    Unfortunately, the evidence implicating the amyloid peptide in mitochondrial damage is more questionable. An interaction between cytoplasmic tau and mitochondria can be easily envisaged, but it is unclear how extracellular or luminal pathological forms of Aβ are able to execute their toxic properties on the mitochondrial organelle. This raises questions about how Aβ becomes translocated across intracellular membranes. Additionally, even if the TOM/TIM complex is able to recruit the Aβ peptide into the mitochondria, the mechanism by which Aβ leads to the decreased enzymatic activity of the electron transport chain remains elusive. Some studies have revealed APP and even the γ-secretase complex in the mitochondria (Crouch et al., 2008; Manczak et al., 2006; Hansson et al., 2004), and in-vitro studies have shown that incubation of synthetic Aβ peptide on cells or on purified mitochondria leads to decreased mitochondrial function (Crouch et al., 2005). If the mitochondrial localization of both APP and the γ-secretase in the mitochondria can be confirmed, then perhaps the mitochondria are indeed capable of producing Aβ peptide locally, but then the question of the physiological function of both proteins in these organelles has to be raised.

    In sum, one could perhaps argue that the “amyloid cascade hypothesis” applies for the familial form of AD, while the “mitochondrial cascade hypothesis” applies for sporadic AD. Eckert and colleagues have attempted to take the field a step forward by studying a triple transgenic AD mouse model to implicate the “mitochondrial cascade hypothesis” in the familial forms of AD, as well. Nevertheless, many conceptual questions remain unanswered, and only time and persistence will lead us to more conclusive answers concerning which “cascade” model is the most correct, meaning, in fact, which hypothesis delivers the most at the level of future medication. As with many things in real life, the truth is probably more mixed than we now anticipate.

    View all comments by Vanessa Morais
  2. The typical feature of AD, i.e., memory loss, is irreversible. In contrast "selective memory loss" of young science writers can—fortunately—be corrected. The model reported by Rhein et al. is not the second but the "nth" with combined amyloid-tau-pathology. I stopped counting around eight (they are not all published, I admit).

    Nevertheless, the data reported by Rhein et al. are most interesting and offer many molecular targets to be tested by researchers in their favorite paradigm, be it patients, mice, cells, fish, flies, or even yeast.

    On the other hand, inclusion of the Swedish mutant APP and the mutant PS2 is now considered not the best option for model-makers, because BACE acts on Swedish APP differently than on wild-type APP. Moreover, mutant PS1/2 do so much more (or less, depending on your gain-of-function or loss-of-function persuasion) than wild-type PS.


    . Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001 Aug 24;293(5534):1487-91. PubMed.

    . Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.

    . Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis. 2005 Dec;20(3):814-22. PubMed.

    . Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am J Pathol. 2007 Dec;171(6):2012-20. PubMed.

    . Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol. 2008 Mar;172(3):786-98. PubMed.

    . Amyloid plaque and neurofibrillary tangle pathology in a regulatable mouse model of Alzheimer's disease. Am J Pathol. 2008 Sep;173(3):762-72. PubMed.

  3. These new triple mice are an improvement over Frank LaFerla's 3xTgAD because a comparison of the tau+ and APP/PS2+ mice to the triples can be made, allowing an examination of synergism and dissection of the relative contributions of each protein to the disease process. At the same time, the co-occurrence of these three mutations is a highly artificial system that does not happen in Alzheimer disease, and therefore one caveat to be considered is the applicability of these findings to sporadic, or even familial, Alzheimer disease.

    With that caveat in mind, the proteomic analysis showed a synergistic effect of β amyloid and tau on mitochondrial function and energy homeostasis. These findings suggest that drugs that improve mitochondrial function, such as methylene blue (Atamna et al., 2008), are potentially promising therapeutics. In addition, the idea that mitochondrial polymorphisms might increase individual susceptibility to Alzheimer disease leaves open the possibility of earlier diagnosis through screening processes.


    . Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. FASEB J. 2008 Mar;22(3):703-12. PubMed.


News Citations

  1. Mitochondria Sag Early in AD Mouse Model

Paper Citations

  1. . Expression of transgenic APP mRNA is the key determinant for beta-amyloid deposition in PS2APP transgenic mice. Neurodegener Dis. 2009;6(1-2):29-36. PubMed.
  2. . Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem. 2001 Jan 5;276(1):529-34. PubMed.
  3. . Phosphorylation of Tau at S422 is enhanced by Abeta in TauPS2APP triple transgenic mice. Neurobiol Dis. 2010 Feb;37(2):294-306. PubMed.
  4. . Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.
  5. . Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem. 2005 Jun 24;280(25):23802-14. PubMed.
  6. . Oligomeric and fibrillar species of beta-amyloid (A beta 42) both impair mitochondrial function in P301L tau transgenic mice. J Mol Med (Berl). 2008 Nov;86(11):1255-67. PubMed.
  7. . Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5. PubMed.
  8. . 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.

Further Reading


  1. . 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.

Primary Papers

  1. . 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.