Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression
Abstract
Alzheimer's disease (AD) is a complex, neurodegenerative disease characterized by the impairment of cognitive function in elderly individuals. In a recent global gene expression study of APP transgenic mice, we found elevated expression of mitochondrial genes, which we hypothesize represents a compensatory response because of mitochondrial oxidative damage caused by the over-expression of mutant APP and/or amyloid beta (Abeta). We investigated this hypothesis in a series of experiments examining what forms of APP and Abeta localize to the mitochondria, and whether the presence of these species is associated with mitochondrial dysfunction and oxidative damage. Using immunoblotting, digitonin fractionation, immunofluorescence, and electron microscopy techniques, we found a relationship between mutant APP derivatives and mitochondria in brain slices from Tg2576 mice and in mouse neuroblastoma cells expressing mutant human APP. Further, to determine the functional relationship between mutant APP/Abeta and oxidative damage, we quantified Abeta levels, hydrogen peroxide production, cytochrome oxidase activity and carbonyl proteins in Tg2576 mice and age-matched wild-type (WT) littermates. Hydrogen peroxide levels were found to be significantly increased in Tg2576 mice when compared with age-matched WT littermates and directly correlated with levels of soluble Abeta in Tg2576 mice, suggesting that soluble Abeta may be responsible for the production of hydrogen peroxide in AD progression in Tg2576 mice. Cytochrome c oxidase activity was found to be decreased in Tg2576 mice when compared with age-matched WT littermates, suggesting that mutant APP and soluble Abeta impair mitochondrial metabolism in AD development and progression. An increase in hydrogen peroxide and a decrease in cytochrome oxidase activity were found in young Tg2576 mice, prior to the appearance of Abeta plaques. These findings suggest that early mitochondrially targeted therapeutic interventions may be effective in delaying AD progression in elderly individuals and in treating AD patients.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Perineuronal net loss in AD may contribute to increased susceptibility to oxidative stress.
“and increased susceptibility to oxidative stress (Deibel et al., 1996; Varadarajan et al., 2000; Manczak et al., 2006; De Felice et al., 2007).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Manczak et al., 2006
APP and Aβ, as well as the entire γ-secretase complex, physically associate with mitochondria and can effect changes in mitochondrial function.
“accumulating data certainly do suggest APP and Aβ, as well as the entire γ-secretase complex, physically associate with mitochondria and can effect changes in mitochondrial function [58-67].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [60]
Cognitive deficits in mild cognitive impairment patients and decreased executive and reasoning abilities in Alzheimer's disease are caused by oxidative damage of small Aβ oligomers to synaptic membranes.
“Cognitive deficits in MCI patients and decreased executive and reasoning abilities in AD are caused by the oxidative damage of small Aβ oligomers to the synaptic membranes [83,84,85].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [85]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
Alzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063 · see citing works
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002) · Nature · doi:10.1038/416535a · Cited by 4,291 · see citing works
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210 · see citing works
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., & Glabe, C. G. (2003) · Science · doi:10.1126/science.1079469 · Cited by 4,064 · see citing works
Pathways towards and Away from Alzheimer’s Disease
Mattson, M. P. (2004) · Nature · doi:10.1038/nature02621 · Cited by 3,052 · see citing works
Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective
Tanzi, R. E., & Bertram, L. (2005) · Cell · doi:10.1016/j.cell.2005.02.008 · Cited by 1,849 · see citing works
Lim, G. P., Chu, T., Yang, F., Beech, W., Frautschy, S. A., & Cole, G. M. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-21-08370.2001 · Cited by 1,530 · see citing works
ENZYMATIC PROPERTIES OF THE INNER AND OUTER MEMBRANES OF RAT LIVER MITOCHONDRIA
Schnaitman, C. A., & Greenawalt, J. W. (1968) · The Journal of Cell Biology · doi:10.1083/jcb.38.1.158 · Cited by 1,390 · see citing works
Mitochondrial abnormalities in Alzheimer's disease
Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R. L., Atwood, C. S., Johnson, A. B., Kress, Y., Vinters, H. V., Tabaton, M., et al. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-09-03017.2001 · Cited by 1,367 · see citing works
ABAD Directly Links Aß to Mitochondrial Toxicity in Alzheimer's Disease
Lustbader, J. W., Cirilli, M., Lin, C., Xu, H. W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., et al. (2004) · Science · doi:10.1126/science.1091230 · Cited by 1,303 · see citing works
Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptide
Butterfield, D. A., Drake, J., Pocernich, C., & Castegna, A. (2001) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(01)02173-6 · Cited by 1,114 · see citing works
Mitochondria take center stage in aging and neurodegeneration
Beal, M. F. (2005) · Annals of Neurology · doi:10.1002/ana.20624 · Cited by 957 · see citing works
Oxidative damage in Alzheimer's
Smith, M. A., Perry, G. L., Richey, P. L., Sayrec, L. M., Anderson, V. E., Beal, M. F., & Kowall, N. W. (1996) · Nature · doi:10.1038/382120b0 · Cited by 897 · see citing works
Praticò, D., Uryu, K., Leight, S., Trojanoswki, J. Q., & Lee, V. M.-Y. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-12-04183.2001 · Cited by 777 · see citing works
A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease
Swerdlow, R. H., & Khan, S. M. (2004) · Medical Hypotheses · doi:10.1016/j.mehy.2003.12.045 · Cited by 758 · see citing works
Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease
Caspersen, C., Wang, N., Yao, J., Sosunov, A., Chen, X., Lustbader, J. W., Xu, H. W., Stern, D., McKhann, G., & Du Yan, S. (2005) · The FASEB Journal · doi:10.1096/fj.05-3735fje · Cited by 738 · see citing works
Kitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N., & LaFerla, F. M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2868-05.2005 · Cited by 697 · see citing works
Helbock, H. J., Beckman, K. B., Shigenaga, M. K., Walter, P. B., Woodall, A., Yeo, H. C. H., & Ames, B. N. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.1.288 · Cited by 688 · see citing works
Water-soluble Aβ(N-40, N-42) oligomers in normal and Alzheimer disease brains
Kuo, Y.-M., Emmerling, M. R., Vigo-Pelfrey, C., Kasunic, T. C., Kirkpatrick, J. B., Murdoch, G. H., Ball, M. J., & Roher, A. E. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.8.4077 · Cited by 618 · see citing works
Anandatheerthavarada, H. K., Biswas, G., Robin, M.-A., & Avadhani, N. G. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200207030 · Cited by 571 · see citing works
Amyloid‐β Deposition in Alzheimer Transgenic Mice Is Associated with Oxidative Stress
Smith, M. A., Hirai, K., Hsiao, K., Pappolla, M. A., Harris, P. L. R., Siedlak, S. L., Tabaton, M., & Perry, G. L. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70052212.x · Cited by 547 · see citing works
β‐Amyloid inhibits integrated mitochondrial respiration and key enzyme activities
Casley, C. S., Canevari, L., Land, J. M., Clark, J. B., & Sharpe, M. A. (2001) · Journal of Neurochemistry · doi:10.1046/j.0022-3042.2001.00681.x · Cited by 485 · see citing works
Mańczak, M., Park, B. S., Jung, Y., & Reddy, P. H. (2004) · NeuroMolecular Medicine · doi:10.1385/nmm:5:2:147 · Cited by 432 · see citing works
Self-citationTemporal Profile of Amyloid-β (Aβ) Oligomerization in an in Vivo Model of Alzheimer Disease
Oddo, S., Caccamo, A., Tran, L., Lambert, M. P., Glabe, C. G., Klein, W. L., & LaFerla, F. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m507892200 · Cited by 379 · see citing works
Differential loss of synaptic proteins in Alzheimer's disease: Implications for synaptic dysfunction
Reddy, P. H., Mani, G., Park, B. S., Jacques, J., MURDOCH, G. H., Whetsell, W. O., Kaye, J. A., & Mańczak, M. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2005-7203 · Cited by 372 · see citing works
Self-citationImmunohistochemical evidence of oxidative [corrected] stress in Alzheimer's disease.
Pappolla, M. A., Omar, R. A., Kim, K. S., & Robakis, N. K. R. K. (1992) · PubMed Central · Cited by 363 · see citing works
Reddy, P. H. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03530.x · Cited by 356 · see citing works
Self-citationRapid accumulation of Akt in mitochondria following phosphatidylinositol 3‐kinase activation
Bijur, G. N., & Jope, R. S. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02113.x · Cited by 332 · see citing works
Pappolla, M. A., Chyan, Y., Omar, R. A., Hsiao, K., Perry, G. L., Smith, M. A., & Bozner, P. (1998) · Europe PMC (PubMed Central) · Cited by 328 · see citing works
Crouch, P. J., Blake, R., Duce, J. A., Ciccotosto, G. D., Li, Q.-X., Barnham, K. J., Curtain, C. C., Cherny, R. A., Cappai, R., Dyrks, T., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4276-04.2005 · Cited by 327 · see citing works
Reddy, P. H., McWeeney, S. K., Park, B. S., Mańczak, M., Gutala, R. V., Partovi, D., Jung, Y., Yau, V., Searles, R. P., Mori, M., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh140 · Cited by 327 · see citing works
Self-citationMetabolism of the “Swedish” Amyloid Precursor Protein Variant in Neuro2a (N2a) Cells
Thinakaran, G., Teplow, D. B., Siman, R., Greenberg, B., & Sisodia, S. S. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.16.9390 · Cited by 317 · see citing works
Are mitochondria critical in the pathogenesis of Alzheimer's disease?
Reddy, P. H., & Beal, M. F. (2005) · Brain Research Reviews · doi:10.1016/j.brainresrev.2005.03.004 · Cited by 289 · see citing works
Self-citationStein, T. D., & Johnson, J. A. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-17-07380.2002 · Cited by 288 · see citing works
Amyloid β-induced Changes in Nitric Oxide Production and Mitochondrial Activity Lead to Apoptosis
Keil, U., Bonert, A., Marques, C. A., Scherping, I., Weyermann, J., Strosznajder, J. B., Müller-Spahn, F., Haass, C., Czech, C., Pradier, L., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405600200 · Cited by 287 · see citing works
Cybrids in Alzheimer's disease: a cellular model of the disease?
Swerdlow, R. H., Parks, J. K., Cassarino, D. S., Maguire, D. J., Maguire, R. S., Bennett, J. P., Davis, R. E., & Parker, W. D. (1997) · Neurology · doi:10.1212/wnl.49.4.918 · Cited by 272 · see citing works
Mitochondria dysfunction of Alzheimer's disease cybrids enhances Aβ toxicity
Cardoso, S. M., Santana, I. J., Swerdlow, R. H., & Oliveira, C. R. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02438.x · Cited by 262 · see citing works
Cybrids in Alzheimer's disease: A cellular model of the disease?
Swerdlow, R. H., & Parker, D. W. (1998) · Neurology · doi:10.1212/wnl.51.1.326-a · Cited by 260 · see citing works
Nicastrin, Presenilin, APH-1, and PEN-2 Form Active γ-Secretase Complexes in Mitochondria
Hansson, C. A., Frykman, S., Farmery, M. R., Tjernberg, L. O., Nilsberth, C., Pursglove, S. E., Ito, A., Winblad, B., Cowburn, R. F., Thyberg, J., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404500200 · Cited by 256 · see citing works
Stackman, R. W., Eckenstein, F., Frei, B., Kulhanek, D., Nowlin, J., & Quinn, J. F. (2003) · Experimental Neurology · doi:10.1016/s0014-4886(03)00399-6 · Cited by 230 · see citing works
Self-citationAleardi, A. M., Benard, G., Augereau, O., Malgat, M., Talbot, J.-C., Mazat, J., Letellier, T., Dachary-Prigent, J., Solaini, G., & Rossignol, R. (2005) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-005-6631-3 · Cited by 225 · see citing works
The synaptic Aβ hypothesis of Alzheimer disease
Tanzi, R. E. (2005) · Nature Neuroscience · doi:10.1038/nn0805-977 · Cited by 206 · see citing works
Functional mitochondria are required for amyloid β‐mediated neurotoxicity
Cardoso, S. M., Santos, S., Swerdlow, R. H., & Oliveira, C. R. (2001) · The FASEB Journal · doi:10.1096/fj.00-0561fje · Cited by 203 · see citing works
Mańczak, M., Jung, Y., Park, B. S., Partovi, D., & Reddy, P. H. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02884.x · Cited by 192 · see citing works
Self-citationAlzheimer's disease cybrids replicate beta-amyloid abnormalities through cell death pathways.
Khan, S. M., Cassarino, D. S., Abramova, N. N., Keeney, P. M., Borland, M. K., Pa, T., Krebs, C. T., Bennett, J. C., Parks, J. K., Swerdlow, R. H., et al. (2000) · PubMed · Cited by 176 · see citing works
Reddy, P. H. (2006) · BioMed Research International · doi:10.1155/jbb/2006/31372 · Cited by 153 · see citing works
Self-citationMigliore, L., Fontana, I., Colognato, R., Coppedè, F., Siciliano, G., & Murri, L. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.10.002 · Cited by 149 · see citing works
Debra Boyd-kimball, A., Castegna, A., Rukhsana Sultana, A., Poon, H. F., Petroze, R. T., Lynn, B. C., Klein, J. B., & Butterfield, D. A. (2005) · Brain Research · doi:10.1016/j.brainres.2005.02.086 · Cited by 142 · see citing works
Abdul, H. M., Rukhsana Sultana, A., Keller, J. N., Clair, D. K. S., Markesbery, W. R., & Butterfield, D. A. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03647.x · Cited by 114 · see citing works
Kokubo, H., Kayed, R., Glabe, C. G., & Yamaguchi, H. (2004) · Brain Research · doi:10.1016/j.brainres.2004.10.041 · Cited by 110 · see citing works
Oxidative stress in Alzheimer's disease
Gibson, G. E., & Huang, H. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.07.017 · Cited by 110 · see citing works
The Amyloid β Protein Induces Oxidative Damage of Mitochondrial DNA
Bozner, P., Grishko, V. I., LeDoux, S. P., Wilson, G. L., CHYAN, Y.-C., & Pappolla, M. A. (1997) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199712000-00010 · Cited by 107 · see citing works
Oxidative modification of proteins in the frontal cortex of Alzheimer's disease brain
Korolainen, M. A., Goldsteins, G., Nyman, T. A., Alafuzoff, I. I., Koıstınaho, J., & Pirttilä, T. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.11.010 · Cited by 103 · see citing works
Oxidative damage as an early marker of Alzheimer's disease and mild cognitive impairment
Beal, M. F. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.09.022 · Cited by 93 · see citing works
Reddy, P. H., & McWeeney, S. K. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.04.014 · Cited by 73 · see citing works
Self-citationγ-Secretase: never more enigmatic
Sisodia, S. S., Annaert, W. G., Kim, S., & Strooper, B. D. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01987-1 · Cited by 58 · see citing works
McEnery, M. W., Dawson, T. M., Verma, A. M., Gurley, D. A., Colombini, M., & Snyder, S. H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)49461-1 · Cited by 43 · see citing works
Peripheral biomarkers of oxidative damage in Alzheimer's disease: the road ahead
Praticò, D. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.09.020 · Cited by 36 · see citing works
Could Aß and AßPP be Antioxidants?
Bush, A. I., Atwood, C., Goldstein, L. E., et al. (2000) · Journal of Alzheimer s Disease · doi:10.3233/jad-2000-2203 · Cited by 7 · see citing works
Khan (2000) · doi:10.1002/1531-8249(200008)48:2
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455 · see citing works
Intracellular amyloid-β in Alzheimer's disease
LaFerla, F. M., Green, K. N., & Oddo, S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2168 · Cited by 1,942 · see citing works
Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease
Tönnies, E., & Trushina, E. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161088 · Cited by 1,750 · see citing works
Bhatti, J. S., Bhatti, G. K., & Reddy, P. H. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.11.010 · Cited by 1,655 · see citing works
Self-citationMitochondria in neuroplasticity and neurological disorders
Mattson, M. P., Gleichmann, M., & Cheng, A. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.010 · Cited by 1,081 · see citing works
Autophagy and apoptosis dysfunction in neurodegenerative disorders
Ghavami, S., Shojaei, S., Yeganeh, B., Ande, S. R., Jangamreddy, J. R., Mehrpour, M., Christoffersson, J., Chaabane, W., Moghadam, A. R., Kashani, H. H., et al. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.10.004 · Cited by 1,039 · see citing works
Oxidative Stress and the Pathogenesis of Alzheimer's Disease
Zhao, Y., & Zhao, B. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/316523 · Cited by 855 · see citing works
Mitochondria and Mitochondrial Cascades in Alzheimer’s disease
Swerdlow, R. H. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170585 · Cited by 850 · see citing works
Wang, X., Su, B., Siedlak, S. L., Moreira, P. I., Fujioka, H., Wang, Y., Casadesus, G., & Zhu, X. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804871105 · Cited by 835 · see citing works
Devi, L., Prabhu, B. M., Galati, D. F., Avadhani, N. G., & Anandatheerthavarada, H. K. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1469-06.2006 · Cited by 792 · see citing works
The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786 · see citing works
History and progress of hypotheses and clinical trials for Alzheimer’s disease
Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0063-8 · Cited by 723 · see citing works
Mitochondrial Defects and Oxidative Stress in Alzheimer Disease and Parkinson Disease
Yan, M. H., Wang, X., & Zhu, X. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.11.014 · Cited by 718 · see citing works
Hansson Petersen, C. A., Alikhani, N., Behbahani, H., Wiehager, B., Pavlov, P. F., Alafuzoff, I., Leinonen, V., Ito, A., Winblad, B., Glaser, E., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806192105 · Cited by 693 · see citing works
Upregulated function of mitochondria‐associated ER membranes in Alzheimer disease
Area‐Gomez, E., del Carmen Lara Castillo, M., Tambini, M. D., Guardia‐Laguarta, C., de Groof, A. J. C., Madra, M., Ikenouchi, J., Umeda, M., Bird, T. D., Sturley, S. L., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.202 · Cited by 638 · see citing works
Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory
Massaad, C. A., & Klann, E. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3208 · Cited by 635 · see citing works
Is Alzheimer’s disease a type 3 diabetes? A critical appraisal
Kandimalla, R., Thirumala, V., & Reddy, P. H. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.08.018 · Cited by 621 · see citing works
Self-citationCaspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease
D'Amelio, M., Cavallucci, V., Middei, S., Marchetti, C., Pacioni, S., Ferri, A., Diamantini, A., De Zio, D., Carrara, P., Battistini, L., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2709 · Cited by 572 · see citing works
Butterfield, D. A., Reed, T., Newman, S. F., & Sultana, R. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.05.037 · Cited by 564 · see citing works
The Alzheimer’s Disease Mitochondrial Cascade Hypothesis
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100339 · Cited by 562 · see citing works
The Role of NMDA Receptors in Alzheimer’s Disease
Liu, J., Chang, L., Song, Y., Li, H., & Wu, Y. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00043 · Cited by 535 · see citing works
Amyloid Beta and Phosphorylated Tau-Induced Defective Autophagy and Mitophagy in Alzheimer’s Disease
Reddy, P. H., & Oliver, D. M. (2019) · Cells · doi:10.3390/cells8050488 · Cited by 496 · see citing works
“In their next paper, Reddy and colleagues [55] tested their hypothesis in a series of experiments examining what forms of APP and Aβ localize to the mitochondria, and whether the presence of these species is associated with mitochondrial dysfunction and oxidative damage.”
BackgroundSelf-citationHedskog, L., Pinho, C. M., Filadi, R., Rönnbäck, A., Hertwig, L., Wiehager, B., Larssen, P., Gellhaar, S., Sandebring, A., Westerlund, M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300677110 · Cited by 478 · see citing works
Sirtuin Functions in Health and Disease
Yamamoto, H., Schoonjans, K., & Auwerx, J. (2007) · Molecular Endocrinology · doi:10.1210/me.2007-0079 · Cited by 480 · see citing works
Amyloid toxicity in Alzheimer’s disease
Reiss, A. B., Arain, H. A., Stecker, M. M., Siegart, N. M., & Kasselman, L. J. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0063 · Cited by 447 · see citing works
McManus, M. J., Murphy, M. P., & Franklin, J. L. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0552-11.2011 · Cited by 432 · see citing works
Reddy, P. H., Tripathi, R., Troung, Q., Tirumala, K., Reddy, T. P., Anekonda, V., Shirendeb, U. P., Calkins, M. J., Reddy, A. P., Mao, P., et al. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.10.011 · Cited by 394 · see citing works
Self-citationDefective mitophagy in Alzheimer’s disease
Pradeepkiran, J. A., & Reddy, P. H. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101191 · Cited by 367 · see citing works
Self-citationManczak, M., & Reddy, P. H. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds360 · Cited by 348 · see citing works
Self-citationOxidative Stress Signaling in Alzheimers Disease
Su, B., Wang, X., Nunomura, A., Moreira, P., Lee, H.-G., Perry, G., Smith, M., & Zhu, X. (2008) · Current Alzheimer Research · doi:10.2174/156720508786898451 · Cited by 344 · see citing works
Causes of oxidative stress in Alzheimer disease
Zhu, X., Su, B., Wang, X., Smith, M. A., & Perry, G. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7218-4 · Cited by 336 · see citing works
RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction
Takuma, K., Fang, F., Zhang, W., Yan, S., Fukuzaki, E., Du, H., Sosunov, A., McKhann, G., Funatsu, Y., Nakamichi, N., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905686106 · Cited by 290 · see citing works
Mitochondria and Calcium in Alzheimer’s Disease: From Cell Signaling to Neuronal Cell Death
Calvo-Rodriguez, M., & Bacskai, B. J. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2020.10.004 · Cited by 254 · see citing works
Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies
Onyango, I. G., Dennis, J., & Khan, S. M. (2016) · Aging and Disease · doi:10.14336/ad.2015.1007 · Cited by 260 · see citing works
Bayer (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00008 · Cited by 252 · see citing works
Mitochondrial Medicine for Aging and Neurodegenerative Diseases
Reddy, P. H. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8044-z · Cited by 230 · see citing works
Self-citationMitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease
Guo, L., Tian, J., & Du, H. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-160702 · Cited by 211 · see citing works
Towards a Better Understanding of GABAergic Remodeling in Alzheimer’s Disease
Govindpani, K., Calvo-Flores Guzmán, B., Vinnakota, C., Waldvogel, H., Faull, R., & Kwakowsky, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081813 · Cited by 208 · see citing works
The Alzheimer's disease mitochondrial cascade hypothesis: an update
Swerdlow, R. H., & Khan, S. M. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.01.011 · Cited by 206 · see citing works
Mitochondrial genes are altered in blood early in Alzheimer's disease
Lunnon, K., Keohane, A., Pidsley, R., Newhouse, S., Riddoch-Contreras, J., Thubron, E. B., Devall, M., Soininen, H., Kłoszewska, I., Mecocci, P., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.12.029 · Cited by 190 · see citing works
Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model
Xie, H., Guan, J., Borrelli, L. A., Xu, J., Serrano-Pozo, A., & Bacskai, B. J. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1836-13.2013 · Cited by 185 · see citing works
“…increased ROS production, altered trafficking, and aberrant fission/fusion regulation when exposed to A (Keller et al., 1997; Mattson et al., 1998; Abramov et al., 2004; Lustbader et al., 2004; Manczak et al., 2006; Wang et al., 2008; Reddy, 2009; Calkins et al., 2011; Manczak et al., 2011).”
BackgroundThe Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders
Wen, T. H., Binder, D. K., Ethell, I. M., & Razak, K. A. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00270 · Cited by 170 · see citing works
The role of mitochondria in inherited neurodegenerative diseases
Kwong, J. Q., Beal, M. F., & Manfredi, G. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03990.x · Cited by 180 · see citing works
Buccellato, F. R., D’Anca, M., Fenoglio, C., Scarpini, E., & Galimberti, D. (2021) · Antioxidants · doi:10.3390/antiox10091353 · Cited by 179 · see citing works
Brahmi (Bacopa monnieri): An ayurvedic herb against the Alzheimer's disease
Dubey, T., & Chinnathambi, S. (2019) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2019.108153 · Cited by 151 · see citing works
Reddy, P. H. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.06.012 · Cited by 147 · see citing works
Self-citationAlzheimer's APP mangles mitochondria
Lin, M. T., & Beal, M. F. (2006) · Nature Medicine · doi:10.1038/nm1106-1241 · Cited by 143 · see citing works
Jayaprakasam, B., Padmanabhan, K., & Nair, M. G. (2010) · Phytotherapy Research · doi:10.1002/ptr.3033 · Cited by 142 · see citing works
A Mitocentric View of Alzheimer's Disease Suggests Multi-Faceted Treatments
Gibson, G. E., & Shi, Q. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-100336 · Cited by 124 · see citing works
Methionine-35 of A <i>β</i> (1–42): Importance for Oxidative Stress in Alzheimer Disease
Butterfield, D. A., & Sultana, R. (2011) · Journal of Amino Acids · doi:10.4061/2011/198430 · Cited by 124 · see citing works
Young, M. L., & Franklin, J. L. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.103409 · Cited by 120 · see citing works
Molecular Basis of Alzheimer’s Disease: Focus on Mitochondria
Oliver, D. M. A., & Reddy, P. H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190048 · Cited by 120 · see citing works
Self-citationReddy, P. H., Manczak, M., & Yin, X. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170051 · Cited by 116 · see citing works
Self-citationLi, B., Liu, J., Gu, G., Han, X., Zhang, Q., & Zhang, W. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15001 · Cited by 110 · see citing works
Delineating the Mechanism of Alzheimer’s Disease Aβ Peptide Neurotoxicity
Cappai, R., & Barnham, K. J. (2008) · Neurochemical Research · doi:10.1007/s11064-007-9469-8 · Cited by 108 · see citing works
Shen, Y., Ye, B., Chen, P., Wang, Q., Fan, C., Shu, Y., & Xiang, M. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00394 · Cited by 105 · see citing works
Bernardo, T. C., Marques‐Aleixo, I., Beleza, J., Oliveira, P. J., Ascensão, A., & Magalhães, J. (2016) · Brain Pathology · doi:10.1111/bpa.12403 · Cited by 108 · see citing works
Yan, L., Guo, M.-S., Zhang, Y., Yu, L., Wu, J.-M., Tang, Y., Ai, W., Zhu, F.-D., Law, B. Y.-K., Chen, Q., et al. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/5288698 · Cited by 97 · see citing works
Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease
Anandatheerthavarada, H. K., & Devi, L. (2007) · The Neuroscientist · doi:10.1177/1073858407303536 · Cited by 95 · see citing works
Park, J., Choi, H., Min, J., Kim, B., Lee, S., Yun, J. W., Choi, M., Chang, K., & Lee, D. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.12984 · Cited by 93 · see citing works
The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics
Pritchard, S. M., Dolan, P. J., Vitkus, A., & Johnson, G. V. W. (2011) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2011.01273.x · Cited by 89 · see citing works
Phloroglucinol Attenuates the Cognitive Deficits of the 5XFAD Mouse Model of Alzheimer’s Disease
Yang, E.-J., Ahn, S., Ryu, J., Choi, M.-S., Choi, S., Chong, Y. H., Hyun, J.-W., Chang, M.-J., & Kim, H.-S. (2015) · PLOS ONE · doi:10.1371/journal.pone.0135686 · Cited by 87 · see citing works
de Dios, C., Abadin, X., Roca-Agujetas, V., Jimenez-Martinez, M., Morales, A., Trullas, R., Mari, M., & Colell, A. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00343-3 · Cited by 85 · see citing works
Neuroinflammation in Alzheimer’s disease: Pleiotropic roles for cytokines and neuronal pentraxins
Swanson, A., Wolf, T., Sitzmann, A., & Willette, A. A. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.02.015 · Cited by 72 · see citing works
An Unbalanced Synaptic Transmission: Cause or Consequence of the Amyloid Oligomers Neurotoxicity?
Sciaccaluga, M., Megaro, A., Bellomo, G., Ruffolo, G., Romoli, M., Palma, E., & Costa, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115991 · Cited by 70 · see citing works
Chen, C.-L., Tsai, W.-H., Chen, C.-J., & Pan, T.-M. (2016) · Journal of Traditional and Complementary Medicine · doi:10.1016/j.jtcme.2015.07.002 · Cited by 69 · see citing works
Sultana, R., Baglioni, M., Cecchetti, R., Cai, J., Klein, J. B., Bastiani, P., Ruggiero, C., Mecocci, P., & Butterfield, D. A. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.08.001 · Cited by 64 · see citing works
A novel lysosome‐to‐mitochondria signaling pathway disrupted by amyloid‐β oligomers
Norambuena, A., Wallrabe, H., Cao, R., Wang, D. B., Silva, A., Svindrych, Z., Periasamy, A., Hu, S., Tanzi, R. E., Kim, D. Y., et al. (2018) · The EMBO Journal · doi:10.15252/embj.2018100241 · Cited by 61 · see citing works
Chakrabarti, M., McDonald, A. J., Will Reed, J., Moss, M. A., Das, B. C., & Ray, S. K. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-150450 · Cited by 57 · see citing works
Pinto, M., Pickrell, A. M., Fukui, H., & Moraes, C. T. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.04.014 · Cited by 47 · see citing works
Adlimoghaddam, A., Odero, G. G., Glazner, G., Turner, R. S., & Albensi, B. C. (2021) · Aging and disease · doi:10.14336/ad.2020.0910 · Cited by 38 · see citing works
Mechanisms of Neuron Loss in Alzheimer’s Disease
Mukhin, V. N., Pavlov, K. I., & Klimenko, V. M. (2017) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-017-0427-x · Cited by 27 · see citing works
Mitochondrial Function and Neurodegenerative Diseases
Wilkins, H. M., Weidling, I., Koppel, S., Wang, X., von Schulze, A., & Swerdlow, R. H. (2018) · The Molecular and Cellular Basis of Neurodegenerative Diseases · doi:10.1016/b978-0-12-811304-2.00013-4 · Cited by 2 · see citing works
- Authors
- Manczak, M., Anekonda, T. S., Henson, E., Park, B. S., Quinn, J., & Reddy, P. H.
- Affiliations
- Oregon Health & Science University (US)
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-03-21
- Volume
- 15
- Issue
- 9
- Pages
- 1437-1449
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2124955411
- Cited by
- 1,104
- References
- 61
- Citations by year
- 2026: 34 · 2025: 41 · 2024: 40 · 2023: 49 · 2022: 44 · 2021: 60 · 2020: 60 · 2019: 51 · 2018: 66 · 2017: 65 · 2016: 67 · 2015: 53 · 2014: 55 · 2013: 63 · 2012: 89
- FWCI
- 30.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- American Federation for Aging Research
- Oregon Health and Science University
- National Institutes of Health
- National Center for Research Resources (S10RR016858, RR-016858)
- National Center for Complementary and Integrative Health (NIH-AT0006)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta, mitochondria, mitochondrial dysfunction, oxidative damage, hydrogen peroxide, cytochrome c oxidase, protein carbonyls, Tg2576 mice, APP transgenic mice, mitochondrial gene expression, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Free Radicals, Humans, Intracellular Membranes, Membrane Potentials, Mice, Transgenic, Mitochondria, Neurons, Peptide Fragments, Amyloid beta-Peptides, Oxidative Stress, Disease Progression, Cell Line, Tumor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
