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The Alzheimer’s Disease Mitochondrial Cascade Hypothesis
Open accessAbstract
We first proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD) in 2004. Our core assumptions were a person's genes determine baseline mitochondrial function and durability, this durability determines how mitochondria change with advancing age, and critical changes in mitochondrial function initiate other pathologies characteristic of AD. Since then several lines of investigation report data consistent with or supportive of our hypothesis. In particular, AD endophenotype studies suggest a strong maternal genetic contribution, and links between mitochondrial function, tau phosphorylation, and amyloid-beta (Abeta) amyloidosis are increasingly recognized. As predicted, AD therapies designed to reduce Abeta thus far have had at best very limited clinical benefits; our hypothesis identifies alternative therapeutic targets. While placing mitochondria at the apex of an AD cascade certainly remains controversial, it is increasingly accepted by the AD research community that mitochondria play an important role in the late-onset forms of the disease. Even if the mitochondrial cascade hypothesis proves incorrect, considering its assumptions could potentially advance our understanding of sporadic, late-onset AD.
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“In contrast to the amyloid cascade hypothesis, which views Aβ as the primary upstream AD biomarker, the mitochondrial cascade hypothesis in general sees Aβ more as a downstream biomarker of brain aging.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“Models based on early-onset, autosomal dominant AD may therefore provide limited insight into late-onset, non-autosomal dominant AD.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“In other words, toxic cascades in AD are not initiated by Aβ, but by mitochondria.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“If correct, the mitochondrial cascade hypothesis has several inconvenient implications. The main implication is that early-onset, autosomal dominant and late-onset, non-autosomal dominant AD cases do not share a common etiology.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“According to the hypothesis Aβ is not an “upstream” biomarker of AD, but is instead a “downstream” marker of evolving mitochondrial dysfunction.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“Accordingly, Aβ deposition within an aging brain simply indicates critical age-related changes are occurring.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“According to the mitochondrial cascade hypothesis, mitochondrial function constitutes the crucial link between brain aging and AD.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“It deviates from the amyloid cascade hypothesis by predicting age-related changes in mitochondrial function, rather than mutations or polymorphisms in APP or Aβ processing genes, primarily account for age-associated brain Aβ changes.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“When mitochondrial decline surpasses a threshold compensatory mechanisms fail and late-onset AD ensues.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“The mitochondrial cascade hypothesis proposes mitochondrial function declines with age, and this decline promotes some features of brain aging including Aβ accumulation.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“The mitochondrial cascade hypothesis proposes mitochondrial function declines with age, and this decline promotes some features of brain aging including Aβ accumulation.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [146]
In the citing paper
“In this explanation, the mitochondrial function declines with age and leads to increased production of ROS [65,66].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [66]
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Citations
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Cited by
Sorted by citations
Oxidative Stress: A Key Modulator in Neurodegenerative Diseases
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“It has been proposed that in sporadic AD mitochondrial dysfunction is the primary event that causes A deposition, synaptic degeneration, and formation of neurofibrillary tangles (Swerdlow et al., 2010).”
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“AD is also associated with inflammatory responses, synaptic damage and mitochondrial structural and functional abnormalities (3-10).”
BackgroundMicroglial cell dysregulation in brain aging and neurodegeneration
von Bernhardi, R., Eugenín-von Bernhardi, L., & Eugenín, J. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00124 · Cited by 556
“…reactive species, and other mediators, contributes to the increased expression of Aβ as well to functional and degenerative changes of neurons, perpetuating abnormal activation of glia, synaptic dysfunction and cell damage. elevated oxidative stress (Swerdlow, 2007; Swerdlow et al., 2010).”
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Sheng, B., Wang, X., Su, B., Lee, H., Casadesús, G., Perry, G. L., & Zhu, X. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07581.x · Cited by 545
“Mitochondria dysfunction plays an important role in AD, but the mechanism is still unclear (Zhu et al. 2004; Reddy and Beal 2005, 2008; Swerdlow 2009; Swerdlow et al. 2010).”
Energy metabolism and inflammation in brain aging and Alzheimer’s disease
Yin, F., Sancheti, H., Patil, I., & Cadenas, E. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.200 · Cited by 538
“The ‘mitochondrial cascade hypothesis’ proposes that in late-onset sporadic AD, the genetic makeup of a person’s electron transport train sets the basis for oxidant production and the tone for oxidative damage, which drives the progression of other pathologies characteristic of AD [4].”
Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies
Rawat, P., Sehar, U., Bisht, J., Selman, A., Culberson, J., & Reddy, P. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112841 · Cited by 509
Estrogen: A master regulator of bioenergetic systems in the brain and body
Rettberg, J. R., Yao, J., & Brinton, R. D. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.08.001 · Cited by 534
“The end result is a vicious cycle in which excessive Ab accumulation and sustained mitochondrial dysfunction synergistically exacerbate each other, leading to activation of a multitude of neurodegenerative pathways (Cardoso et al., 2004; Silva et al., 2011; Swerdlow et al., 2010; Yao et al., 2011).”
Impaired mitochondrial function in psychiatric disorders
Manji, H. K., Kato, T., Prospero, N. A. D., Ness, S. L., Beal, M. F., Krams, M., & Chen, G. (2012) · Nature reviews. Neuroscience · doi:10.1038/nrn3229 · Cited by 493
Mitochondrial Diseases of the Brain
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“hypothesis” mitochondrial dysfunction is the primary event in pathogenesis of AD[241].”
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“Maternally transmitted mtDNA abnormalities, if confirmed, would act as an upstream event in NL individuals with AD-affected mothers, whereas mitochondrial damage secondary to AD pathology would be more likely in LOAD cases caused by factors other than mtDNA changes.”
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Mosconi, L., Berti, V., Quinn, C., McHugh, P., Petrongolo, G., Varsavsky, I., Osorio, R. S., Pupi, A., Vallabhajosula, S., Isaacson, R. S., et al. (2017) · Neurology · doi:10.1212/wnl.0000000000004425 · Cited by 319
The Therapeutic Potential of Metformin in Neurodegenerative Diseases
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“Energy metabolism and mitochondrial dysfunction have been proposed as a primary event in mechanisms underlying AD such as synaptic degeneration, Aβ deposition and formation of neurofibrillary tangles (325).”
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Swerdlow, R. H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.08.012 · Cited by 306
“An alternative to the amyloid cascade hypothesis [141 – 143], the mitochondrial cascade hypothesis [123,146 – 148], sees brain aging and AD as part of a continuum.”
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“In summary, our study observations suggest that hippocampal accumulation of mutant APP and Ab responsible for (1) cognitive impairments, (2) abnormal mitochondrial dynamics (increased fission and decreased fusion), (3) defective biogenesis, (4) reduced autophagy/mitophagy, (4) loss of dendritic protein MAP2, (5) dendr…”
BackgroundInfluentialRetractedMechanistic insights and perspectives involved in neuroprotective action of quercetin
Grewal, A. K., Singh, T. G., Sharma, D., Sharma, V., Singh, M., Rahman, M. H., Najda, A., Walasek-Janusz, M., Kamel, M. S., Albadrani, G. M., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111729 · Cited by 295
Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca 2+ cross-talk
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“This finding, together with the generally accepted concept that mitochondrial deficits are key events in most neurodegenerative diseases (16, 17), and more specifically in AD (18, 19), led us to investigate the effect of presenilins on ER–mitochondria cross-talk.”
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“Mitochondrial dysfunction is a prominent feature of both familial and sporadic Alzheimer’s disease (AD) and plays an important role in AD pathophysiology (1,2).”
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“In the current study, we tested the hypothesis that mitochondrial trafficking defects would occur in vivo as a consequence of tau over-expression and/or its mislocalization and aggregation, and also asked whether defects in mitochondrial trafficking could be detected in human AD.”
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Scheyer, O., Rahman, A., Hristov, H., Berkowitz, C., Isaacson, R. S., Diaz Brinton, R., & Mosconi, L. (2018) · The Journal of Prevention of Alzheimer's Disease · doi:10.14283/jpad.2018.34 · Cited by 268
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Mitochondrial Aspects of Synaptic Dysfunction in Alzheimer’s Disease
Cai, Q., & Tammineni, P. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160726 · Cited by 281
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“An increased production of ROS, such as hydrogen peroxide, seen in mitochondrial dysfunction also leads to an activation of PLA2 provoking further myelin breakdown (Adibhatla and Hatcher, 2008; Sun et al., 2010; Yao et al., 2011).”
BackgroundInfluentialMitochondrial Calcium: Effects of Its Imbalance in Disease
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“In addition, AD is also associated with synaptic damage and loss of synapses, abnormal mitochondrial structural and functional alterations and the proliferation of reactive astrocytes and microglia and neuronal loss (1, 3-5, 9-12).”
RetractedAbnormal Mitochondrial Dynamics in the Pathogenesis of Alzheimer's Disease
Zhu, X., Perry, G., Smith, M. A., & Wang, X. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-129005 · Cited by 242
“Mitochondrial dynamics are regulated by a delicate fusion mitochondrial fission [17].”
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Molecular and Cellular Basis of Neurodegeneration in Alzheimer’s Disease
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“Mitochondrial dysfunction in the brains of AD patients correlates with a wide range of mitochondrial abnormalities including mitochondrial DNA defects, decreased levels of mitochondrial enzyme activities, impaired mitochondrial trafficking, and increased oxidative stress (Reddy and Reddy, 2011; Swerdlow et al., 2010).”
BackgroundInfluentialSoluble forms of tau are toxic in Alzheimer's disease
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Is Alzheimer’s disease a systemic disease?
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AMP‐activated protein kinase: a potential player in Alzheimer’s disease
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Oxidant/Antioxidant Imbalance in Alzheimer’s Disease: Therapeutic and Diagnostic Prospects
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Deubiquitinating enzymes regulate PARK2-mediated mitophagy
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Alterations in Mitochondrial Quality Control in Alzheimer’s Disease
Cai, Q., & Tammineni, P. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00024 · Cited by 226
“…prominent mitochondria-related anomalies in AD include the accumulation of damaged mitochondria in both familial and sporadic forms of the disease (Swerdlow et al., 2010), as well as changes in mitochondrial structure, dynamics, and motility in vulnerable neurons of affected brain regions…”
BackgroundLow cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease
Podlesniy, P., Figueiro‐Silva, J., Llado, A., Antonell, A., Sanchez‐Valle, R., Alcolea, D., Lleo, A., Molinuevo, J. L., Serra, N., & Trullas, R. (2013) · Annals of Neurology · doi:10.1002/ana.23955 · Cited by 219
“Converging evidence indicates that AD is associated with alterations in bioenergetics and mitochondrial function.(13,14) Neurons are highly dependent on aerobic energy provided by mitochondria, which contain several copies of their own DNA (mtDNA).”
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“Ab signaling is linked with peroxynitrite production.(1,15) Ab or peroxynitrite trigger mitochondrial fragmentation, which in turn can lead to bioenergetic failure, impaired Ca2þ homeostasis, synaptic injury, axonal transport defects and neuronal cell death.”
BackgroundMitochondrial Dysfunction: a Potential Therapeutic Target to Treat Alzheimer’s Disease
Nand, S., Singh, C., Singh, A., Singh, M. P., & Singh, S. P. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01945-y · Cited by 217
Mitochondrial Dysfunction: Different Routes to Alzheimer’s Disease Therapy
Picone, P., Nuzzo, D., Caruana, L., Scafidi, V., & Carlo, M. D. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/780179 · Cited by 219
“Many lines of evidence suggest that the mitochondrion plays a central role in neurodegenerative diseases, including AD [2], and the so called mitochondrial cascade hypothesis proposes that mitochondrial dysfunction is the primary event in AD pathology [3].”
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Cellular Proteostasis in Neurodegeneration
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The role of mitochondrial dysfunction in age-related diseases
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“It has been hypothesized that part of the maternal bias may be due to the unequal inheritance of COX genes; while most subunits are encoded by nuclear DNA, three are inherited from the mother's mtDNA [43].”
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“Apolipoprotein E4 (1-272) fragment is associ-”
BackgroundBrain-Derived Neurotrophic Factor and Alzheimer’s Disease: Physiopathology and Beyond
Diniz, B. S., & Teixeira, A. L. (2011) · NeuroMolecular Medicine · doi:10.1007/s12017-011-8154-x · Cited by 211
Alzheimer's Disease: Redox Dysregulation As a Common Denominator for Diverse Pathogenic Mechanisms
Rommy von Bernhardi, M., & Eugenín, J. L. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4082 · Cited by 193
“C), one on the new hypothesis for the pathogenesis of AD (617, 618).”
BackgroundPerimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery
Mosconi, L., Berti, V., Quinn, C. G., McHugh, P. F., Petrongolo, G., Osorio, R. S., Connaughty, C., Pupi, A., Vallabhajosula, S., Isaacson, R., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0185926 · Cited by 185
Multifactorial Hypothesis and Multi-Targets for Alzheimer’s Disease
Gong, C., Liu, F., & Iqbal, K. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179921 · Cited by 188
Amyloid Beta: Multiple Mechanisms of Toxicity and Only Some Protective Effects?
Carrillo‐Mora, P., Luna, R., & Colín-Barenque, L. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/795375 · Cited by 187
“All this evidence recently led to propose the mitochondrial cascade hypothesis of AD, which holds that inherited mitochondrial genes, mitochondrial dysfunction associated with aging, and deficiency in antioxidant mechanisms coupled with a low intake of exogenous antioxidants, promote a severe redox imbalance, thus res…”
BackgroundBuccellato, F. R., D’Anca, M., Fenoglio, C., Scarpini, E., & Galimberti, D. (2021) · Antioxidants · doi:10.3390/antiox10091353 · Cited by 179
Quantitative profiling brain proteomes revealed mitochondrial dysfunction in Alzheimer’s disease
Adav, S. S., Park, J. E., & Sze, S. K. (2019) · Molecular Brain · doi:10.1186/s13041-019-0430-y · Cited by 183
Freeman, L. R., & Keller, J. N. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.12.009 · Cited by 181
“One of the contributing factors that is common to many neurodegenerative diseases involving oxidative stress pathways is mitochondrial dysfunction [12-16].”
Role of mitochondrial homeostasis and dynamics in Alzheimer's disease
Selfridge, J. E., E, L., Lu, J., & Swerdlow, R. H. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.12.057 · Cited by 175
Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses
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“…progression of the disease; whereas in the late-onset sporadic AD, mitochondrial dysfunction hypothesis suggests that mitochondrial defect is the primary factor for triggering the accumulation of Aβ and the formation of NFTs, thereby resulting in synaptic degradation and neuronal death [115, 116].”
BackgroundFiladi, R., Greotti, E., Turacchio, G., Luini, A., Pozzan, T., & Pizzo, P. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.013 · Cited by 173
“, 2009), metabolic defects (Swerdlow et al., 2010), or altered organelle distribution in neurons (Su et al.”
BackgroundBerman, M. H., Halper, J. P., Nichols, T. W., Jarrett, H., Lundy, A., & Huang, J. H. (2017) · Journal of Neurology and Neuroscience · doi:10.21767/2171-6625.1000176 · Cited by 168
“Mitochondrial dysfunction has important roles in the neurodegenerative cascade [10].”
BackgroundSynaptic Change in the Posterior Cingulate Gyrus in the Progression of Alzheimer's Disease
Scheff, S. W., PRICE, D. A., Ansari, M. A., Roberts, K. N., Schmitt, F. A., Ikonomović, M. D., & Mufson, E. J. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-141518 · Cited by 169
“Other important early factors that could impact synapse dysfunction include neuroinflammation [113–118], mitochondrial dysfunction [119–125], oxidative stress [126–130], cerebrovascular dysfunction [131–133], tau modification [8, 134–136], and epigenetics.”
Petrov, D., Pedrós, I., Artiach, G., Sureda, F. X., Barroso, E., Pallàs, M., Casadesús, G., Beas-Zarate, C., Carro, E., Ferrer, I., et al. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.05.004 · Cited by 163
“This view has recently been expanded [42–44] and is supported by a number of studies (reviewed in [45]) which classify AD as a primarily metabolic disorder.”
Defective Autophagy and Mitophagy in Aging and Alzheimer’s Disease
Tran, M., & Reddy, P. H. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.612757 · Cited by 167
“Mitochondrial Dysfunction in Alzheimer’s Disease Another common finding in AD postmortem brains is signs of oxidative damage and mitochondrial dysfunction (Reddy, 2007; Swerdlow et al., 2010).”
BackgroundOxidative stress, cellular senescence and ageing
Pole, A., Dimri, M., & Dimri, G. P. (2016) · AIMS molecular science · doi:10.3934/molsci.2016.3.300 · Cited by 168
“Another perspective corresponds to a more age-related mitochondrial dysfunction as the primary root cause from an accumulation of mt DNA mutations as well as affecting tau protein functionality [137].”
BackgroundMorris, G., Berk, M., Carvalho, A. F., Maes, M. H. J., Walker, A. J., & Puri, B. K. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.12.036 · Cited by 155
“Such evidence includes the accumulation of profoundly damaged mitochondria [330], as well as adverse changes in mitochondrial dynamics, motility, autophagy and structure, in stressed neurones of the hippocampus [331,332].”
Seneff, S., & Samsel, A. (2015) · Surgical Neurology International · doi:10.4103/2152-7806.153876 · Cited by 170
“These neurological disorders are associated with mitochondrial impairment([197,241,243,281,316]) and with excess glutamate and ammonia in the brain,([2,109,265]) leading to a chronic low-grade encephalopathy.”
BackgroundKumar, A., & Singh, A. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00206 · Cited by 157
“When Aβ peptides accumulates in mitochondria it causes inhibition of mitochondrial respiratory enzyme complex-II and IV, causes decreased production of ATP and an increased production of ROS mitochondrial dysfunction in AD (Figure 1, Rhein et al., 2009; Swerdlow et al., 2010).”
BackgroundInfluentialMitochondrial import and degradation of amyloid-β peptide
Pinho, C. M., Teixeira, P. F., & Glaser, E. G. (2014) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2014.02.007 · Cited by 149
Ferretti, M. T., Martínková, J., Biskup, E. M., Benke, T., Gialdini, G., Nedelská, Z., Rauen, K., Mantua, V., Religa, D., Hort, J., et al. (2020) · European Journal of Neurology · doi:10.1111/ene.14174 · Cited by 152
“Mitochondrial cascade has been proposed as one of the alternatives to the traditional amyloid hypothesis in the genesis of sporadic AD [81,82].”
BackgroundMultiple faces of dynamin-related protein 1 and its role in Alzheimer's disease pathogenesis
Kandimalla, R. J. L., & Reddy, P. H. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.12.018 · Cited by 148
The role of mitochondria in neurodegenerative diseases
Filosto, M., Scarpelli, M., Cotelli, M. S., Vielmi, V., Todeschini, A., Gregorelli, V., Tonin, P., Tomelleri, G., & Padovani, A. (2011) · Journal of Neurology · doi:10.1007/s00415-011-6104-z · Cited by 142
“Vice versa, Ab production should be the primary event in autosomal dominant AD in which it could trigger mitochondrial dysfunction [36].”
InfluentialMonteiro-Cardoso, V. F., Oliveira, M. M., Melo, T., Domingues, M. R., Moreira, P. I., Ferreiro, E. B., Peixoto, F., & Videira, R. A. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-141002 · Cited by 141
“: +351 259350273; Fax: +351 259 350 480; E-mail: rvideira@utad.pt.”
Du, L., Chai, D., Zhao, L., Li, X.-H., Zhang, F.-C., Zhang, H., Liu, L.-B., Wu, K., Liu, R., Wang, J., et al. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140564 · Cited by 141
“Additionally, mitochondria play a crucial role in regulating neuronal cell survival and death, and dysfunctional mitochondria contribute to the etiology of AD [30, 38, 39].”
Current perspectives on potential role of albumin in neuroprotection
Prajapati, K. D., Sharma, S. S., & Roy, N. (2011) · Reviews in the Neurosciences · doi:10.1515/rns.2011.028 · Cited by 137
Mitochondrial Dysfunction in Alzheimer’s Disease: A Biomarker of the Future?
Bell, S., Barnes, K., Marco, M. D., Shaw, P. J., Ferraiuolo, L., Blackburn, D. J., Venneri, A., & Mortiboys, H. (2021) · Biomedicines · doi:10.3390/biomedicines9010063 · Cited by 138
“It remains unclear if the functional and structural changes to the ETC seen in AD are a result of a primary mitochondrial change, as suggested in the mitochondrial hypothesis of AD [70], or a consequence of the build-up of amyloid within the brain and body of AD patients.”
BackgroundEmerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease
Salminen, A., Kaarniranta, K., Haapasalo, A., Hiltunen, M., Soininen, H., & Alafuzoff, I. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.11.005 · Cited by 153
Paglia, G., Stocchero, M., Cacciatore, S., Lai, S., Angel, P. M., Alam, M. T., Keller, M. A., Ralser, M., & Astarita, G. (2015) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b01020 · Cited by 136
Tewari, D., Stankiewicz, A. M., Mocan, A., Sah, A. N., Tzvetkov, N. T., Huminiecki, Ł., Horbańczuk, J. O., & Atanasov, A. G. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00003 · Cited by 142
“The mitochondrial cascade hypothesis proposed the mitochondrial dysfunction as a principal episode in AD pathology (Moreira et al., 2010; Swerdlow et al., 2010).”
BackgroundA high-glycemic diet is associated with cerebral amyloid burden in cognitively normal older adults
Taylor, M. K., Sullivan, D. K., Swerdlow, R. H., Vidoni, E. D., Morris, J. K., Mahnken, J. D., & Burns, J. M. (2017) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.117.162263 · Cited by 145
“Protein homeostasis requires a steady flux of energy; bioenergetic perturbations that arise due to elevated glycemia and insulin resistance may potentially contribute to altered amyloid precursor protein or b-amyloid processing (38).”
BackgroundMastroeni, D., Khdour, O. M., Delvaux, E., Nolz, J., Olsen, G., Berchtold, N. C., Cotman, C. W., Hecht, S. M., & Coleman, P. D. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.09.003 · Cited by 134
“Among the significant proponents of the “mitochondrial cascade hypothesis” have been RH Swerdlow [44] and MF Beal [45].”
BackgroundSilva, D. F., Selfridge, J. E., Lu, J., E, L., Roy, N., Hutfles, L., Burns, J. M., Michaelis, E. K., Yan, S., Cardoso, S. M., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt247 · Cited by 133
“Mitochondrial dysfunction may, therefore, drive or mediate various AD pathologies (5).”
BackgroundResultZhang, J., Cao, Q., Li, S., Lu, X., Zhao, Y., Guan, J., Chen, J., Wu, Q., & Chen, G. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.06.043 · Cited by 130
Genome instability in Alzheimer disease
Hou, Y., Song, H., Croteau, D. L., Akbari, M., & Bohr, V. A. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.04.005 · Cited by 120
“Additionally, a mitochondrial cascade hypothesis for AD (Swerdlow et al., 2010; Swerdlow and Khan, Mech Ageing Dev.”
BackgroundMitochondrial dysfunction and Alzheimer's disease
Maruszak, A., & Żekanowski, C. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.07.004 · Cited by 124
Yao, J., Rettberg, J. R., Klosinski, L. P., Cadenas, E., & Brinton, R. D. (2011) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2011.10.005 · Cited by 125
“This creates a vicious cycle in which excessive Aβ accumulation and sustained mitochondrial dysfunction synergize to activate a cascade of neurodegenerative pathways (Silva et al., 2011; Swerdlow et al., 2010; Swerdlow and Khan, 2004, 2009).”
BackgroundPolydoro, M., Dzhala, V. I., Pooler, A. M., Nicholls, S. B., McKinney, A. P., Sanchez, L., Pitstick, R., Carlson, G. A., Staley, K. J., Spires-Jones, T. L., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-013-1215-5 · Cited by 117
“Indeed, recent studies suggest that more soluble forms of tau, rather than fibrillar tangles, may be involved in neuronal dysfunction [28, 29, 44, 45, 50, 63].”
BackgroundCell Death and NeurodegenerationPreprint
Andreone, B. J., Larhammar, M., & Lewcock, J. W. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a036434 · Cited by 124
“Increasing evidence suggests that mitochondrial dysfunction is a cause of neurodegeneration, rather than a consequence, and may contribute to disease pathology and neuronal loss in both AD and PD (Devi et al. 2008; Chinta et al. 2010; Swerdlow et al. 2010; Dawson and Dawson 2017).”
BackgroundDynamics of Human Mitochondrial Complex I Assembly: Implications for Neurodegenerative Diseases
Giachin, G., Bouverot, R., Acajjaoui, S., Pantalone, S., & Soler‐López, M. (2016) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2016.00043 · Cited by 118
Effect of ApoE isoforms on mitochondria in Alzheimer disease
Yin, J., Reiman, E. M., Beach, T. G., Serrano, G. E., Sabbagh, M. N., Nielsen, M., Caselli, R. J., & Shi, J. (2020) · Neurology · doi:10.1212/wnl.0000000000009582 · Cited by 116
“Since a mitochondrial cascade hypothesis was proposed in 2004,(20) it is increasingly suspected that mitochondrial dysfunction plays a detrimental role in AD.(21) Mitochondrial dysfunction has been identified as an early event in AD pathogenesis,(5) and enhancing mitochondrial function may attenuate pathologic changes…”
BackgroundInfluentialMulti-Targets: An Unconventional Drug Development Strategy for Alzheimer’s Disease
Gong, C., Dai, C., Liu, F., & Iqbal, K. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.837649 · Cited by 109
Mitochondria-derived peptides in aging and healthspan
Miller, B., Kim, S.-J., Kumagai, H., Yen, K., & Cohen, P. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158449 · Cited by 121
New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases
Scarian, E., Viola, C., Dragoni, F., Gerlando, R. D., Rizzo, B., Diamanti, L., Gagliardi, S., Bordoni, M., & Pansarasa, O. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052698 · Cited by 118
Mitochondria, Cybrids, Aging, and Alzheimer's Disease
Swerdlow, R. H., Koppel, S., Weidling, I., Hayley, C., Ji, Y., & Wilkins, H. M. (2017) · Progress in Molecular Biology and Translational Science · doi:10.1016/bs.pmbts.2016.12.017 · Cited by 106
Fossati, S., Giannoni, P., Solesio, M. E., Cocklin, S. L., Cabrera, E., Ghiso, J. A., & Rostagno, A. A. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.11.006 · Cited by 107
Alzheimer’s Disease: Etiology, Neuropathology and Pathogenesis
Sheppard, O., & Coleman, M. P. (2020) · Exon Publications eBooks · doi:10.36255/exonpublications.alzheimersdisease.2020.ch1 · Cited by 127
Dilmore, A. H., Martino, C., Neth, B. J., West, K., Zemlin, J., Rahman, G., Panitchpakdi, M. W., Meehan, M. J., Weldon, K. C., Blach, C., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13007 · Cited by 108
“However, it is now appreciated that a variety of systemic changes occur throughout the course of AD, including metabolic dysregulation (3, 4), mitochondrial dysfunction (5, 6), inflammation (7), and body compositional changes (8, 9).”
BackgroundQuantification of the Brain Proteome in Alzheimer’s Disease Using Multiplexed Mass Spectrometry
Musunuri, S., Wetterhall, M., Ingelsson, M., Lannfelt, L., Artemenko, K. A., Bergquist, J., Kultima, K., & Shevchenko, G. (2014) · Journal of Proteome Research · doi:10.1021/pr401202d · Cited by 103
Current progress of mitochondrial transplantation that promotes neuronal regeneration
Chang, C.-Y., Liang, M.-Z., & Chen, L. (2019) · Translational Neurodegeneration · doi:10.1186/s40035-019-0158-8 · Cited by 102
Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?
Peggion, C., Calí, T., & Brini, M. (2024) · Antioxidants · doi:10.3390/antiox13020240 · Cited by 112
“Taking into consideration all the abovementioned mitochondrial dysfunctions in AD, in addition to the most popular amyloid hypothesis for AD pathogenesis, some authors have proposed the mitochondrial hypothesis [19,60,61].”
Background
Metadata
- Authors
- Swerdlow, R. H., Burns, J. M., & Khan, S. M.
- Affiliations
- University of Kansas (US)
- Gencia (United States) (US)
- Corresponding author
- Swerdlow, Russell H.
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2010-06-03
- Volume
- 20
- Issue
- s2
- Pages
- S265-S279
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC2883665
- OpenAlex
- W1685999671
- Cited by
- 562
- References
- 145
- Citations by year
- 2026: 31 · 2025: 30 · 2024: 26 · 2023: 63 · 2022: 34 · 2021: 37 · 2020: 38 · 2019: 25 · 2018: 36 · 2017: 37 · 2016: 41 · 2015: 31 · 2014: 33 · 2013: 37 · 2012: 28
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG026374, R21AG029615, AG029615, AG022407, R01AG022407, R03AG026374)
- National Eye Institute (R21EY018474, EY018474)
- National Institute of Neurological Disorders and Stroke (K23NS058252)
- National Center for Research Resources (M01RR023940)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- MeSH terms
- Aging, Alzheimer Disease, Animals, Electron Transport Complex IV, DNA, Mitochondrial, Humans, Mitochondria, Models, Biological, Amyloid beta-Peptides
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