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Manczak M, Calkins MJ, Reddy PH. Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. Hum Mol Genet. 2011 Jul 1;20(13):2495-509. PubMed.
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University of Kansas
In this paper, the Reddy lab presents additional evidence of an Aβ-mitochondrial nexus. They report that mitochondrial fission-fusion is imbalanced in AD subject brains and in transgenic mice expressing human mutant β APP. The human brain work is particularly welcome, as it provides both message- and protein-level data for genes and their protein products that mediate mitochondrial fission (Drp and Fis1) and fusion (Mfn1, Mfn2, Opa1, and Tomm40). The essential findings are that, in the AD brain, mitochondrial fission seems to be ratcheted up while fusion seems to be ratcheted down. Moreover, through several approaches, the authors showed that a physical relationship exists between Drp and Aβ oligomers.
Overall, these data are in agreement with other related AD mitochondrial fission-fusion studies, although some divergence from earlier reports is noted. Perhaps the key divergence is from data from Xiongwei Zhu’s lab that found Drp is reduced in AD brains. No doubt future studies will further clarify AD mitochondrial fission-fusion function and resolve these details.
Where does this work fit into the big picture? Regardless of whether Aβ ultimately causes AD, if it is part of a degenerative cascade, the question remains whether its role in the cascade reflects extra- or intracellular effects. Moreover, if the effects are indeed intracellular, then what is the nature of that effect? In this respect, the field has come a long way since Cardoso et al. first published experimental data that compellingly made the case that Aβ toxicity is mediated intracellularly and through a mitochondrial interaction.
Finally, in this paper, Manczak et al. discuss their work’s therapeutic development implications. Let’s put aside for a minute the possibility that mitochondria may actually mediate changes in amyloid, as opposed to the dynamic evaluated in almost all AD modeling studies, which is that Aβ must mediate changes in mitochondrial function. If brain Aβ oligomers are toxic because they disrupt mitochondrial physiology in general, and the fission-fusion apparatus specifically, then preventing the responsible associations is a reasonable therapeutic approach. The question arises, though, as to whether interventions designed primarily to remove extracellular Aβ can substantially impact these associations.
References:
Cardoso SM, Santos S, Swerdlow RH, Oliveira CR. Functional mitochondria are required for amyloid beta-mediated neurotoxicity. FASEB J. 2001 Jun;15(8):1439-41. PubMed.
Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X. Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci. 2009 Jul 15;29(28):9090-103. PubMed.
Weill Cornell Medical College
This manuscript provides further data that point to dysfunctional mitochondria in AD. The authors measured a number of proteins that play a critical role in mitochondrial dynamics and turnover. They found that there is increased dynamin-related peptide (DRP1) in the AD brain, which is consistent with the findings of others. This is a peptide that mediates mitochondrial fission. Fis1, the receptor for DRP1, was also increased, and mitochondrial fusion peptides (mitofuscins and OPA1) were reduced. Interestingly, they show an association of Aβ monomers with DRP1.
The work of Lipton and colleagues showed that DRP1 was nitrosylated, which resulted in increased GTPase activity, although some other authors have not seen this. Increased mitochondrial fission is associated with apoptotic cell death. The findings worsened with disease progression. CypD (cyclophilin D), which is linked to the mitochondrial transition pore, was increased.
This is of interest, since Du and Yan showed that CypD deficiency attenuates cell death and memory impairment in an AD mouse model (Du et al., 2008). It would have been nice to see counts of mitochondria in tangle-bearing neurons, such as we recently reported for Huntington's disease in which grade-dependent increases in DRP1 were associated with reduced numbers of mitochondria in vulnerable neurons (Kim et al., 2010). Nevertheless, the present findings provide strong support for mitochondrial dysfunction and impaired mitochondrial dynamics in AD.
References:
Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med. 2008 Oct;14(10):1097-105. PubMed.
Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Beal MF, Ferrante RJ. Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease. Hum Mol Genet. 2010 Oct 15;19(20):3919-35. Epub 2010 Jul 21 PubMed.
Case Western Reserve University
It is increasingly accepted that abnormal mitochondrial dynamics likely underlie mitochondrial dysfunction in AD. Despite some discrepancy with the prior publications from our group, this is an interesting paper that adds important in vivo evidence supporting the notion that the balance of mitochondrial fission and fusion is tipped towards more fission in the AD brain. This study also confirmed the likely involvement of abnormal mitochondrial distribution (i.e., decreased mitochondrial distribution in neuronal processes). The most important and novel contribution of this study is the finding of physical interaction between Drp1 and Aβ (both monomeric and oligomeric) and APP in a AD-specific manner. Prior studies suggested/implicated that Aβ induces enhanced mitochondrial fission through enhanced ROS production and/or calcium changes; this study implicates that a direct interaction may also come into play. However, it remains to be determined where the Aβ (APP)-Drp1 interaction occurs, and how such interaction affects Drp1 activity and/or mitochondrial translocation and eventually mitochondrial morphology and function.
The discrepancy between the current study and our prior publications is in the expression of Drp1 in AD. We found no changes in mRNA level and significantly reduced Drp1 protein in AD and in APP overexpressing neurons (Wang et al., 2008a, 2008b, 2009), while Reddy reported increased mRNA and proteins of Drp1 in both AD and APP transgenic mice (Manczak et al., 2010 and this report). We found decreased mitochondrial distribution in neuronal processes in AD cell models, which is also confirmed in Reddy’s study, and we demonstrated that Drp1 reduction likely underlies such abnormal mitochondrial distribution. It is unclear what causes the inconsistencies. Given the variation in the levels of Drp1 in control and in AD samples in these studies, larger sample sizes of well-characterized cases should be used in the future studies to resolve such discrepancies.
References:
Wang X, Su B, Fujioka H, Zhu X. Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer's disease patients. Am J Pathol. 2008 Aug;173(2):470-82. PubMed.
Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23. PubMed.
Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X. Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci. 2009 Jul 15;29(28):9090-103. PubMed.
Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, Murphy MP, Szeto HH, Park B, Reddy PH. Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer's disease neurons. J Alzheimers Dis. 2010;20 Suppl 2:S609-31. PubMed.
University of Kansas
In recent decades, our knowledge of mitochondrial dysfunction in Alzheimer’s disease (AD) has rapidly expanded. The recognition of mitochondrial dynamics and trafficking alterations in AD greatly broadens our understanding of mitochondrial distress in Alzheimer’s. The other recent paper by Reddy’s group (Calkins et al., 2011) showed the disturbances of mitochondrial fusion/fission proteins in APP/ADDL overexpression cell lines and AD brains, and revealed the imbalance of mitochondrial fusion/fission proteins is an important mechanism underlying synaptic degeneration and neuronal stress in AD brains. Previously, Xionwei Zhu and colleagues demonstrated the significance of mitochondrial fusion/fission in Aβ-induced neuronal dysfunction (Wang et al., 2008; Wang et al., 2009). These findings lead the way for studies into mitochondrial behavioral change and its relation to neuronal dysfunction in AD.
It is noted that among the many mitochondrial fusion/fission proteins, dynamin-related protein 1 (Drp1) plays a critical role in initiating mitochondrial fission by its translocation from the cytosol to the mitochondrial outer membrane. Besides the observation of changes in Drp1 and Drp1 expression levels in AD, Lipton’s group demonstrated that the S-nitrosylation of Drp1 is another mechanism of increased mitochondrial fission in the AD brain, which ultimately leads to neuronal death. Reddy’s recent paper introduced a new mechanism regarding the role of Drp1 in AD brains, in that Drp1 interacts with amyloid-β in both monomeric and oligomeric forms, and the interaction increases with disease progression. This finding implicates the close correlation of Drp1 functional abnormality with amyloid-β toxicity, which not only serves as new evidence of AD mitochondrial pathology, but also provides new thoughts of AD treatment. This work also confirmed kinetic changes in some mitochondrial proteins in human AD at different stages, such as increased cyclophilin D expression as observed from our laboratory. The results from Reddy’s studies enhance our understanding of the role of Drp1 in AD pathology and add to our exploration into mitochondrial medicine as a potential approach to intervene in the pathogenesis of AD.
References:
Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23. PubMed.
Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X. Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci. 2009 Jul 15;29(28):9090-103. PubMed.
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