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.

References:
Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001 Aug 24;293(5534):1487-91. Abstract

Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, Laferla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. Abstract

Ribé EM, Pérez M, Puig B, Gich I, Lim F, Cuadrado M, Sesma T, Catena S, Sánchez B, Nieto M, Gómez-Ramos P, Morán MA, Cabodevilla F, Samaranch L, Ortiz L, Pérez A, Ferrer I, Avila J, Gómez-Isla T. Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis. 2005 Dec;20(3):814-22. Abstract

Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M, Lewis J, Hutton M, Tolnay M, Jucker M. 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. Abstract

Terwel D, Muyllaert D, Dewachter I, Borghgraef P, Croes S, Devijver H, Van Leuven F. Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol. 2008 Mar;172(3):786-98. Abstract

Paulson JB, Ramsden M, Forster C, Sherman MA, McGowan E, Ashe KH. Amyloid plaque and neurofibrillary tangle pathology in a regulatable mouse model of Alzheimer's disease. Am J Pathol. 2008 Sep;173(3):762-72. Abstract

View all comments by Fred Van Leuven

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.

References:
Atamna, H., A. Nguyen, C. Schultz, K. Boyle, J. Newberry, H. Kato, and B. N. Ames. 2008. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. FASEB J. 22 (3):703-712. Abstract

View all comments by Miranda Reed

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...  Read more

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.

References:
Stoothoff W, Jones PB, Spires-Jones TL, Joyner D, Chhabra E, Bercury K, Fan Z, Xie H, Bacskai B, Edd J, Irimia D, Hyman BT. (2009) Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport. J Neurochem. Oct;111(2):417-27. 19686388

Swerdlow, R.H., Khan, S.M. (2004) A “mitochondrial cascade hypothesis” for sporadic Alzheimer's disease. Med. Hypotheses 63, 8–20. 15193340

Escobar-Khondiker, M., Hollerhage, M., Muriel, M.P., Champy, P., Bach, A., Depienne, C., Respondek, G., Yamada, E.S., Lannuzel, A., Yagi, T., Hirsch, E.C., Oertel, W.H., Jacob, R., Michel, P.P., Ruberg, M., Hoglinger, G.U. (2007) Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. J.Neurosci. 27, 7827–7837. 17634376

Hansson Petersen CA, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, Alafuzoff I, Leinonen V, Ito A, Winblad B, Glaser E, Ankarcrona M. (2008) The amyloid beta peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc. Natl. Acad. Sci. U. S. A. 105, 13145-13150. 18757748

Manczak, M., Anekonda, T.S., Henson, E., Park, B.S., Quinn, J., Reddy, P.H. (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet. 15, 1437-1449. 16551656

Hansson CA, Frykman S, Farmery MR, Tjernberg LO, Nilsberth C, Pursglove SE, Ito A, Winblad B, Cowburn RF, Thyberg J, Ankarcrona M. (2004) Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. J Biol Chem., Dec 3;279(49):51654-60. 15456764

Cherny, R.A., Cappai, R., Dyrks, T., Masters, C.L., Trounce, I.A. (2005) Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42. J. Neurosci. 25, 672-679. 15659604

View all comments by Vanessa Morais