Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains.
[en] Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger of Alzheimer's disease (AD) pathology. Altered mitochondrial homeostasis is considered an early event in AD development. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established. Here, we demonstrate in neuroblastoma SH-SY5Y cells expressing either APP Swedish mutations, or the β-secretase-derived APP-CTF fragment (C99) combined with β- and γ-secretase inhibition, that APP-CTFs accumulation independently of Aβ triggers excessive mitochondrial morphology alteration (i.e., size alteration and cristae disorganization) associated with enhanced mitochondrial reactive oxygen species production. APP-CTFs accumulation also elicit basal mitophagy failure illustrated by enhanced conversion of LC3, accumulation of LC3-I and/or LC3-II, non-degradation of SQSTM1/p62, inconsistent Parkin and PINK1 recruitment to mitochondria, enhanced levels of membrane and matrix mitochondrial proteins, and deficient fusion of mitochondria with lysosomes. We confirm the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo in young 3xTgAD transgenic mice treated with γ-secretase inhibitor as well as in adeno-associated-virus-C99 injected mice. Comparison of aged 2xTgAD and 3xTgAD mice indicates that, besides APP-CTFs, an additional contribution of Aβ to late-stage mitophagy activation occurs. Importantly, we report on mitochondrial accumulation of APP-CTFs in human post-mortem sporadic AD brains correlating with mitophagy failure molecular signature. Since defective mitochondria homeostasis plays a pivotal role in AD pathogenesis, targeting mitochondrial dysfunctions and/or mitophagy by counteracting early APP-CTFs accumulation may represent relevant therapeutic interventions in AD.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Vaillant-Beuchot, Loan ✱
MARY, Arnaud ✱; Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of excellence DistALZ, 660 route des Lucioles,6560, Sophia-Antipolis, Valbonne, France.
✱ These authors have contributed equally to this work.
External co-authors :
yes
Language :
English
Title :
Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains.
Allen GF, Toth R, James J, Ganley IG (2013) Loss of iron triggers PINK1/Parkin-independent mitophagy. EMBO Rep 14:1127–1135. 10.1038/embor.2013.168 DOI: 10.1038/embor.2013.168
Anandatheerthavarada HK, Devi L (2007) Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease. Neuroscientist 13:626–638. 10.1177/1073858407303536 DOI: 10.1177/1073858407303536
Anandatheerthavarada HK, Devi L (2007) Mitochondrial translocation of amyloid precursor protein and its cleaved products: relevance to mitochondrial dysfunction in Alzheimer's disease. Rev Neurosci 18:343–354. 10.1177/1073858407303536 DOI: 10.1177/1073858407303536
Area-Gomez E, Del Carmen Lara Castillo M, Tambini MD, Guardia-Laguarta C, de Groof AJ, Madra M et al (2012) Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J 31:4106–4123. 10.1038/emboj.2012.202 DOI: 10.1038/emboj.2012.202
Asai M, Yagishita S, Iwata N, Saido TC, Ishiura S, Maruyama K (2011) An alternative metabolic pathway of amyloid precursor protein C-terminal fragments via cathepsin B in a human neuroglioma model. FASEB J 25:3720–3730. 10.1096/fj.11-182154 DOI: 10.1096/fj.11-182154
Berger-Sweeney J, McPhie DL, Arters JA, Greenan J, Oster-Granite ML, Neve RL (1999) Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Res Mol Brain Res 66:150–162. 10.1016/s0169-328x(99)00014-5 DOI: 10.1016/s0169-328x(99)00014-5
Bittner T, Fuhrmann M, Burgold S, Jung CK, Volbracht C, Steiner H et al (2009) Gamma-secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway. J Neurosci 29:10405–10409. 10.1523/JNEUROSCI.2288-09.2009 DOI: 10.1523/JNEUROSCI.2288-09.2009
Bobba A, Amadoro G, Valenti D, Corsetti V, Lassandro R, Atlante A (2013) Mitochondrial respiratory chain Complexes I and IV are impaired by beta-amyloid via direct interaction and through Complex I-dependent ROS production, respectively. Mitochondrion 13:298–311. 10.1016/j.mito.2013.03.008 DOI: 10.1016/j.mito.2013.03.008
Bolte S, Cordelieres FP (2006) A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 224:213–232. 10.1111/j.1365-2818.2006.01706.x DOI: 10.1111/j.1365-2818.2006.01706.x
Boon WC, van den Buuse M, Wegener N, Martin S, Chua HK, Bush AI et al (2010) Behavioural phenotype of APPC100.V717F transgenic mice over-expressing a mutant Abeta-bearing fragment is associated with reduced NMDA receptor density. Behav Brain Res 209:27–35. 10.1016/j.bbr.2010.01.013 DOI: 10.1016/j.bbr.2010.01.013
Bourgeois A, Lauritzen I, Lorivel T, Bauer C, Checler F, Pardossi-Piquard R (2018) Intraneuronal accumulation of C99 contributes to synaptic alterations, apathy-like behavior, and spatial learning deficits in 3xTgAD and 2xTgAD mice. Neurobiol Aging 71:21–31. 10.1016/j.neurobiolaging.2018.06.038 DOI: 10.1016/j.neurobiolaging.2018.06.038
Bussiere R, Lacampagne A, Reiken S, Liu X, Scheuerman V, Zalk R et al (2017) Amyloid beta production is regulated by beta2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor. J Biol Chem 292:10153–10168. 10.1074/jbc.M116.743070 DOI: 10.1074/jbc.M116.743070
Checler F (1995) Processing of the beta-amyloid precursor protein and its regulation in Alzheimer's disease. J Neurochem 65:1431–1444. 10.1046/j.1471-4159.1995.65041431.x DOI: 10.1046/j.1471-4159.1995.65041431.x
Chen JX, Yan SS (2010) Role of mitochondrial amyloid-beta in Alzheimer's disease. J Alzheimers Dis 20(Suppl 2):S569–578. 10.3233/JAD-2010-100357 DOI: 10.3233/JAD-2010-100357
Christensen DZ, Bayer TA, Wirths O (2009) Formic acid is essential for immunohistochemical detection of aggregated intraneuronal Abeta peptides in mouse models of Alzheimer's disease. Brain Res 1301:116–125. 10.1016/j.brainres.2009.09.014 DOI: 10.1016/j.brainres.2009.09.014
Cummins N, Tweedie A, Zuryn S, Bertran-Gonzalez J, Gotz J (2019) Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria. EMBO J. 10.15252/embj.201899360 DOI: 10.15252/embj.201899360
da Costa CA, Ancolio K, Checler F (2000) Wild-type but not Parkinson's disease-related ala-53 → Thr mutant alpha-synuclein protects neuronal cells from apoptotic stimuli. J Biol Chem 275:24065–24069. 10.1074/jbc.M002413200 DOI: 10.1074/jbc.M002413200
De Strooper B, Karran E (2016) The cellular phase of Alzheimer's disease. Cell 164:603–615. 10.1016/j.cell.2015.12.056 DOI: 10.1016/j.cell.2015.12.056
Del Prete D, Suski JM, Oules B, Debayle D, Gay AS, Lacas-Gervais S et al (2017) Localization and processing of the amyloid-beta protein precursor in mitochondria-associated membranes. J Alzheimers Dis 55:1549–1570. 10.3233/JAD-160953 DOI: 10.3233/JAD-160953
Devi L, Ohno M (2012) Mitochondrial dysfunction and accumulation of the beta-secretase-cleaved C-terminal fragment of APP in Alzheimer's disease transgenic mice. Neurobiol Dis 45:417–424. 10.1016/j.nbd.2011.09.001 DOI: 10.1016/j.nbd.2011.09.001
Duchen MR, Surin A, Jacobson J (2003) Imaging mitochondrial function in intact cells. Methods Enzymol 361:353–389 DOI: 10.1016/S0076-6879(03)61019-0
Dunys J, Valverde A, Checler F (2018) Are N- and C-terminally truncated Abeta species key pathological triggers in Alzheimer's disease? J Biol Chem 293:15419–15428. 10.1074/jbc.R118.003999 DOI: 10.1074/jbc.R118.003999
Emmerzaal TL, Rodenburg RJ, Tanila H, Verweij V, Kiliaan AJ, Kozicz T (2018) Age-dependent decrease of mitochondrial complex II activity in a familial mouse model for Alzheimer's disease. J Alzheimers Dis 66:75–82. 10.3233/JAD-180337 DOI: 10.3233/JAD-180337
Evin G, Zhu A, Holsinger RM, Masters CL, Li QX (2003) Proteolytic processing of the Alzheimer's disease amyloid precursor protein in brain and platelets. J Neurosci Res 74:386–392. 10.1002/jnr.10745 DOI: 10.1002/jnr.10745
Falcon-Perez JM, Nazarian R, Sabatti C, Dell'Angelica EC (2005) Distribution and dynamics of Lamp1-containing endocytic organelles in fibroblasts deficient in BLOC-3. J Cell Sci 118:5243–5255. 10.1242/jcs.02633 DOI: 10.1242/jcs.02633
Fedeli C, Filadi R, Rossi A, Mammucari C, Pizzo P (2019) PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca(2+) homeostasis. Autophagy 15:2044–2062. 10.1080/15548627.2019.1596489 DOI: 10.1080/15548627.2019.1596489
Fivenson EM, Lautrup S, Sun N, Scheibye-Knudsen M, Stevnsner T et al (2017) Mitophagy in neurodegeneration and aging. Neurochem Int 109:202–209. 10.1016/j.neuint.2017.02.007 DOI: 10.1016/j.neuint.2017.02.007
Flammang B, Pardossi-Piquard R, Sevalle J, Debayle D, Dabert-Gay AS, Thevenet A et al (2012) Evidence that the amyloid-beta protein precursor intracellular domain, AICD, derives from beta-secretase-generated C-terminal fragment. J Alzheimers Dis 30:145–153. 10.3233/JAD-2012-112186 DOI: 10.3233/JAD-2012-112186
Flannery PJ, Trushina E (2019) Mitochondrial dynamics and transport in Alzheimer's disease. Mol Cell Neurosci 98:109–120. 10.1016/j.mcn.2019.06.009 DOI: 10.1016/j.mcn.2019.06.009
Goiran T, Duplan E, Chami M, Bourgeois A, El Manaa W, Rouland L et al (2017) Beta-amyloid precursor protein intracellular domain controls mitochondrial function by modulating phosphatase and tensin homolog-induced kinase 1 transcription in cells and in Alzheimer mice models. Biol Psychiatry. 10.1016/j.biopsych.2017.04.011 DOI: 10.1016/j.biopsych.2017.04.011
Goiran T, Duplan E, Rouland L, El Manaa W, Lauritzen I, Dunys J et al (2018) Nuclear p53-mediated repression of autophagy involves PINK1 transcriptional down-regulation. Cell Death Differ 25:873–884. 10.1038/s41418-017-0016-0 DOI: 10.1038/s41418-017-0016-0
Gonzalez AE, Munoz VC, Cavieres VA, Bustamante HA, Cornejo VH, Januario YC et al (2017) Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of thesoso amyloid precursor protein via the MVB/lysosomal pathway. FASEB J 31:2446–2459. 10.1096/fj.201600713R DOI: 10.1096/fj.201600713R
Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach M et al (2009) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 30:1574–1586. 10.1016/j.neurobiolaging.2007.12.005 DOI: 10.1016/j.neurobiolaging.2007.12.005
Hu Y, Li XC, Wang ZH, Luo Y, Zhang X, Liu XP et al (2016) Tau accumulation impairs mitophagy via increasing mitochondrial membrane potential and reducing mitochondrial Parkin. Oncotarget 7:17356–17368. 10.18632/oncotarget.7861 DOI: 10.18632/oncotarget.7861
Hung COY, Livesey FJ (2018) Altered gamma-secretase processing of APP disrupts lysosome and autophagosome function in monogenic Alzheimer's disease. Cell Rep 25(3647–3660):e3642. 10.1016/j.celrep.2018.11.095 DOI: 10.1016/j.celrep.2018.11.095
Jazvinscak Jembrek M, Slade N, Hof PR, Simic G (2018) The interactions of p53 with tau and Ass as potential therapeutic targets for Alzheimer's disease. Prog Neurobiol 168:104–127. 10.1016/j.pneurobio.2018.05.001 DOI: 10.1016/j.pneurobio.2018.05.001
Jiang Y, Sato Y, Im E, Berg M, Bordi M, Darji S et al (2019) Lysosomal dysfunction in down syndrome is APP-dependent and mediated by APP-betaCTF (C99). J Neurosci 39:5255–5268. 10.1523/JNEUROSCI.0578-19.2019 DOI: 10.1523/JNEUROSCI.0578-19.2019
Kaur G, Pawlik M, Gandy SE, Ehrlich ME, Smiley JF, Levy E (2017) Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein. Mol Psychiatry 22:981–989. 10.1038/mp.2016.189 DOI: 10.1038/mp.2016.189
Kim SH, Vlkolinsky R, Cairns N, Lubec G (2000) Decreased levels of complex III core protein 1 and complex V beta chain in brains from patients with Alzheimer's disease and Down syndrome. Cell Mol Life Sci 57:1810–1816. 10.1007/pl00000661 DOI: 10.1007/pl00000661
Kwart D, Gregg A, Scheckel C, Murphy EA, Paquet D, Duffield M et al (2019) A Large panel of isogenic APP and PSEN1 mutant human iPSC neurons reveals shared endosomal abnormalities mediated by APP beta-CTFs, not abeta. Neuron 104:1022. 10.1016/j.neuron.2019.11.010 DOI: 10.1016/j.neuron.2019.11.010
Lauritzen I, Becot A, Bourgeois A, Pardossi-Piquard R, Biferi MG, Barkats M et al (2019) Targeting gamma-secretase triggers the selective enrichment of oligomeric APP-CTFs in brain extracellular vesicles from Alzheimer cell and mouse models. Transl Neurodegener 8:35. 10.1186/s40035-019-0176-6 DOI: 10.1186/s40035-019-0176-6
Lauritzen I, Pardossi-Piquard R, Bauer C, Brigham E, Abraham JD, Ranaldi S et al (2012) The beta-secretase-derived C-terminal fragment of betaAPP, C99, but not abeta, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J Neurosci 32:16243–16255. 10.1523/JNEUROSCI.2775-12.2012 DOI: 10.1523/JNEUROSCI.2775-12.2012
Lauritzen I, Pardossi-Piquard R, Bourgeois A, Becot A, Checler F (2019) Does intraneuronal accumulation of carboxyl-terminal fragments of the amyloid precursor protein trigger early neurotoxicity in Alzheimer's disease? Curr Alzheimer Res 16:453–457. 10.2174/1567205016666190325092841 DOI: 10.2174/1567205016666190325092841
Lauritzen I, Pardossi-Piquard R, Bourgeois A, Pagnotta S, Biferi MG, Barkats M et al (2016) Intraneuronal aggregation of the beta-CTF fragment of APP (C99) induces Abeta-independent lysosomal-autophagic pathology. Acta Neuropathol 132:257–276. 10.1007/s00401-016-1577-6 DOI: 10.1007/s00401-016-1577-6
Leuner K, Muller WE, Reichert AS (2012) From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer's disease. Mol Neurobiol 46:186–193. 10.1007/s12035-012-8307-4 DOI: 10.1007/s12035-012-8307-4
Lonskaya I, Shekoyan AR, Hebron ML, Desforges N, Algarzae NK, Moussa CE (2013) Diminished parkin solubility and co-localization with intraneuronal amyloid-beta are associated with autophagic defects in Alzheimer's disease. J Alzheimers Dis 33:231–247. 10.3233/JAD-2012-121141 DOI: 10.3233/JAD-2012-121141
Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N et al (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science 304:448–452. 10.1126/science.1091230 DOI: 10.1126/science.1091230
Manczak M, Calkins MJ, Reddy PH (2011) 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 20:2495–2509. 10.1093/hmg/ddr139 DOI: 10.1093/hmg/ddr139
Manczak M, Kandimalla R, Yin X, Reddy PH (2018) Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease. Hum Mol Genet 27:1332–1342. 10.1093/hmg/ddy042 DOI: 10.1093/hmg/ddy042
Martin-Maestro P, Gargini R, Perry G, Avila J, Garcia-Escudero V (2016) PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease. Hum Mol Genet 25:792–806. 10.1093/hmg/ddv616 DOI: 10.1093/hmg/ddv616
Mitani Y, Yarimizu J, Saita K, Uchino H, Akashiba H, Shitaka Y et al (2012) Differential effects between gamma-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci 32:2037–2050. 10.1523/JNEUROSCI.4264-11.2012 DOI: 10.1523/JNEUROSCI.4264-11.2012
Mondragon-Rodriguez S, Gu N, Manseau F, Williams S (2018) Alzheimer's transgenic model is characterized by very early brain network alterations and beta-CTF fragment accumulation: reversal by beta-secretase inhibition. Front Cell Neurosci 12:121. 10.3389/fncel.2018.00121 DOI: 10.3389/fncel.2018.00121
Nalbantoglu J, Tirado-Santiago G, Lahsaini A, Poirier J, Goncalves O, Verge G et al (1997) Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387:500–505. 10.1038/387500a0 DOI: 10.1038/387500a0
Nhan HS, Chiang K, Koo EH (2015) The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta Neuropathol 129:1–19. 10.1007/s00401-014-1347-2 DOI: 10.1007/s00401-014-1347-2
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R et al (2003) Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39:409–421. 10.1016/S0896-6273(03)00434-3 DOI: 10.1016/S0896-6273(03)00434-3
Osellame LD, Blacker TS, Duchen MR (2012) Cellular and molecular mechanisms of mitochondrial function. Best Pract Res Clin Endocrinol Metab 26:711–723. 10.1016/j.beem.2012.05.003 DOI: 10.1016/j.beem.2012.05.003
Oster-Granite ML, McPhie DL, Greenan J, Neve RL (1996) Age-dependent neuronal and synaptic degeneration in mice transgenic for the C terminus of the amyloid precursor protein. J Neurosci 16:6732–6741 DOI: 10.1523/JNEUROSCI.16-21-06732.1996
Oules B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J et al (2012) Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci 32:11820–11834. 10.1523/JNEUROSCI.0875-12.2012 DOI: 10.1523/JNEUROSCI.0875-12.2012
Pagani L, Eckert A (2011) Amyloid-Beta interaction with mitochondria. Int J Alzheimers Dis 2011:925050. 10.4061/2011/925050 DOI: 10.4061/2011/925050
Pavlov PF, Wiehager B, Sakai J, Frykman S, Behbahani H, Winblad B et al (2011) Mitochondrial gamma-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein. FASEB J 25:78–88. 10.1096/fj.10-157230 DOI: 10.1096/fj.10-157230
Pera M, Alcolea D, Sanchez-Valle R, Guardia-Laguarta C, Colom-Cadena M, Badiola N et al (2013) Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease. Acta Neuropathol 125:201–213. 10.1007/s00401-012-1062-9 DOI: 10.1007/s00401-012-1062-9
Pera M, Larrea D, Guardia-Laguarta C, Montesinos J, Velasco KR, Agrawal RR et al (2017) Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J 36:3356–3371. 10.15252/embj.201796797 DOI: 10.15252/embj.201796797
Pickles S, Vigie P, Youle RJ (2018) Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol 28:R170–R185. 10.1016/j.cub.2018.01.004 DOI: 10.1016/j.cub.2018.01.004
Piras A, Collin L, Gruninger F, Graff C, Ronnback A (2016) Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol Commun 4:22. 10.1186/s40478-016-0292-9 DOI: 10.1186/s40478-016-0292-9
Pulina MV, Hopkins M, Haroutunian V, Greengard P, Bustos V (2020) C99 selectively accumulates in vulnerable neurons in Alzheimer's disease. Alzheimers Dement 16:273–282. 10.1016/j.jalz.2019.09.002 DOI: 10.1016/j.jalz.2019.09.002
Rah JC, Kim HS, Kim SS, Bach JH, Kim YS, Park CH et al (2001) Effects of carboxyl-terminal fragment of Alzheimer's amyloid precursor protein and amyloid beta-peptide on the production of cytokines and nitric oxide in glial cells. FASEB J 15:1463–1465. 10.1096/fj.00-0724fje DOI: 10.1096/fj.00-0724fje
Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med 14:45–53. 10.1016/j.molmed.2007.12.002 DOI: 10.1016/j.molmed.2007.12.002
Reddy PH, Yin X, Manczak M, Kumar S, Pradeepkiran JA, Vijayan M et al (2018) Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease. Hum Mol Genet 27:2502–2516. 10.1093/hmg/ddy154 DOI: 10.1093/hmg/ddy154
Robinson KM, Janes MS, Pehar M, Monette JS, Ross MF, Hagen TM et al (2006) Selective fluorescent imaging of superoxide in vivo using ethidium-based probes. Proc Natl Acad Sci USA 103:15038–15043. 10.1073/pnas.0601945103 DOI: 10.1073/pnas.0601945103
Rojansky R, Cha MY, Chan DC (2016) Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. Elife. 10.7554/eLife.17896 DOI: 10.7554/eLife.17896
Rossi MJ, Pekkurnaz G (2019) Powerhouse of the mind: mitochondrial plasticity at the synapse. Curr Opin Neurobiol 57:149–155. 10.1016/j.conb.2019.02.001 DOI: 10.1016/j.conb.2019.02.001
Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray JM et al (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228:35–51. 10.1016/0009-8981(94)90055-8 DOI: 10.1016/0009-8981(94)90055-8
Schreiner B, Hedskog L, Wiehager B, Ankarcrona M (2015) Amyloid-beta peptides are generated in mitochondria-associated endoplasmic reticulum membranes. J Alzheimers Dis 43:369–374. 10.3233/JAD-132543 DOI: 10.3233/JAD-132543
Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158–167. 10.1016/j.molcel.2012.09.025 DOI: 10.1016/j.molcel.2012.09.025
Sorrentino V, Romani M, Mouchiroud L, Beck JS, Zhang H, D'Amico D et al (2017) Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity. Nature 552:187–193. 10.1038/nature25143 DOI: 10.1038/nature25143
Tamayev R, D'Adamio L (2012) Inhibition of gamma-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia. Mol Neurodegener 7:19. 10.1186/1750-1326-7-19 DOI: 10.1186/1750-1326-7-19
van Dyck CH (2018) Anti-amyloid-beta monoclonal antibodies for Alzheimer's disease: pitfalls and promise. Biol Psychiatry 83:311–319. 10.1016/j.biopsych.2017.08.010 DOI: 10.1016/j.biopsych.2017.08.010
Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y et al (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 105:19318–19323. 10.1073/pnas.0804871105 DOI: 10.1073/pnas.0804871105
Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Biochim Biophys Acta 1842:1240–1247. 10.1016/j.bbadis.2013.10.015 DOI: 10.1016/j.bbadis.2013.10.015
Wang Y, Wu F, Pan H, Zheng W, Feng C, Wang Y et al (2016) Lost region in amyloid precursor protein (APP) through TALEN-mediated genome editing alters mitochondrial morphology. Sci Rep 6:22244. 10.1038/srep22244 DOI: 10.1038/srep22244
Wilkins HM, Swerdlow RH (2017) Amyloid precursor protein processing and bioenergetics. Brain Res Bull 133:71–79. 10.1016/j.brainresbull.2016.08.009 DOI: 10.1016/j.brainresbull.2016.08.009
Xu LL, Shen Y, Wang X, Wei LF, Wang P, Yang H et al (2017) Mitochondrial dynamics changes with age in an APPsw/PS1dE9 mouse model of Alzheimer's disease. NeuroReport 28:222–228. 10.1097/WNR.0000000000000739 DOI: 10.1097/WNR.0000000000000739
Yang C, Cai CZ, Song JX, Tan JQ, Durairajan SSK, Iyaswamy A et al (2017) NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models. Autophagy 13:2028–2040. 10.1080/15548627.2017.1379633 DOI: 10.1080/15548627.2017.1379633
Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 245:417–420. 10.1126/science.2474201 DOI: 10.1126/science.2474201
Ye X, Sun X, Starovoytov V, Cai Q (2015) Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains. Hum Mol Genet 24:2938–2951. 10.1093/hmg/ddv056 DOI: 10.1093/hmg/ddv056
Yoo SM, Jung YK (2018) A molecular approach to mitophagy and mitochondrial dynamics. Mol Cells 41:18–26. 10.14348/molcells.2018.2277 DOI: 10.14348/molcells.2018.2277
Zhang L, Trushin S, Christensen TA, Bachmeier BV, Gateno B, Schroeder A et al (2016) Altered brain energetics induces mitochondrial fission arrest in Alzheimer's disease. Sci Rep 6:18725. 10.1038/srep18725 DOI: 10.1038/srep18725
