The Alzheimer's disease mitochondrial cascade hypothesis: An update

In 2004 we proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD). Our hypothesis assumed sporadic and autosomal dominant AD are not etiologically homogeneous, considered evidence that AD pathology is not brain-limited, and incorporated aging theory. The mitochondrial cascade hypothesis asserted: (1) inheritance determines mitochondrial baseline function and durability; (2) mitochondrial durability influences how mitochondria change with age; and (3) when mitochondrial change reaches a threshold, AD histopathology and symptoms ensue. We now review the reasoning used to formulate the hypothesis, discuss pertinent interim data, and update its tenants. Readers are invited to consider the conceptual strengths and weaknesses of this hypothesis.

[1]  J. Wands,et al.  Mitochondrial DNA Damage as a Mechanism of Cell Loss in Alzheimer's Disease , 2000, Laboratory Investigation.

[2]  R. Mahley,et al.  Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[3]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[4]  A D Roses,et al.  Complex disease-associated pharmacogenetics: drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer's disease) , 2007, The Pharmacogenomics Journal.

[5]  P. Davies,et al.  Mitotic mechanisms in Alzheimer's disease? , 1996, The Journal of cell biology.

[6]  Xi Chen,et al.  Materials and Methods Som Text Figs. S1 and S2 Table S1 References Abad Directly Links A␤ to Mitochondrial Toxicity in Alzheimer's Disease , 2022 .

[7]  Xiongwei Zhu,et al.  Elevated expression of a regulator of the G2/M phase of the cell cycle, neuronal CIP‐1‐associated regulator of cyclin B, in Alzheimer's disease , 2004, Journal of neuroscience research.

[8]  P. Mecocci,et al.  Oxidative damage to mitochondrial DNA shows marked age‐dependent increases in human brain , 1993, Annals of neurology.

[9]  G. Schellenberg,et al.  Candidate gene for the chromosome 1 familial Alzheimer's disease locus , 1995, Science.

[10]  C. Cotman,et al.  Caspase-9 Activation and Caspase Cleavage of tau in the Alzheimer's Disease Brain , 2002, Neurobiology of Disease.

[11]  B. Winblad,et al.  Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. , 2004, The Journal of biological chemistry.

[12]  J. Hardy,et al.  Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. , 1996, Nature medicine.

[13]  R. Urbanics,et al.  A chronic Alzheimer’s model evoked by mitochondrial poison sodium azide for pharmacological investigations , 2004, Behavioural Brain Research.

[14]  N Howell,et al.  Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. Gilbert,et al.  Analysis of European mitochondrial haplogroups with Alzheimer disease risk , 2004, Neuroscience Letters.

[16]  S. Thibodeau,et al.  Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. , 1996, The New England journal of medicine.

[17]  Patrizia Mecocci,et al.  Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease , 1994, Annals of neurology.

[18]  D. Guertin,et al.  Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex , 2005, Science.

[19]  X. Chen,et al.  Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  B. Winblad,et al.  Association study of two genetic variants in mitochondrial transcription factor A (TFAM) in Alzheimer's and Parkinson's disease , 2007, Neuroscience Letters.

[21]  Gabriele Siciliano,et al.  Mitochondrial cascade hypothesis of Alzheimer's disease: myth or reality? , 2007, Antioxidants & redox signaling.

[22]  S. Kish,et al.  Decreased Brain Protein Levels of Cytochrome Oxidase Subunits in Alzheimer's Disease and in Hereditary Spinocerebella Ataxia Disorders , 1999, Journal of neurochemistry.

[23]  T. Arendt,et al.  Aneuploidy and DNA Replication in the Normal Human Brain and Alzheimer's Disease , 2007, The Journal of Neuroscience.

[24]  H. Reichmann,et al.  Pathophysiology of the MELAS 3243 Transition Mutation* , 1997, The Journal of Biological Chemistry.

[25]  John X. Morris,et al.  The Fat of the Land: Do Agricultural Subsidies Foster Poor Health? , 2004, BMC Genetics.

[26]  Mark P. Mattson,et al.  Apoptosis in neurodegenerative disorders , 2000, Nature Reviews Molecular Cell Biology.

[27]  S. Rapoport,et al.  Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease. , 1994, Brain research. Molecular brain research.

[28]  C. Cotman,et al.  Apoptosis Decision Cascades and Neuronal Degeneration in Alzheimer’s Disease , 1998, Neurobiology of Aging.

[29]  Rachel L. Mistur,et al.  Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism , 2007, Proceedings of the National Academy of Sciences.

[30]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[31]  S. Hirai,et al.  Ultrastructural localization of Alzheimer amyloid β/A4 protein precursor in the cytoplasm of neurons and senile plaque-associated astrocytes , 2004, Acta Neuropathologica.

[32]  K. Herrup,et al.  DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease , 2001, The Journal of Neuroscience.

[33]  S. Lovestone,et al.  The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. , 1997, Neuroscience.

[34]  J. Schneider,et al.  Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration , 2007, Acta Neuropathologica.

[35]  G. Binetti,et al.  Effect of energy shortage and oxidative stress on amyloid precursor protein metabolism in COS cells , 1997, Neuroscience Letters.

[36]  C. Bondy,et al.  Signaling by insulin-like growth factor 1 in brain. , 2004, European journal of pharmacology.

[37]  Hirokazu Fukui,et al.  Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease , 2007, Proceedings of the National Academy of Sciences.

[38]  R. Swerdlow.  Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? , 2007, Neurobiology of Aging.

[39]  P. Cohen,et al.  The renaissance of GSK3 , 2001, Nature Reviews Molecular Cell Biology.

[40]  R. Swerdlow,et al.  Alzheimer's disease cybrids replicate β‐amyloid abnormalities through cell death pathways , 2000 .

[41]  M. Billingsley,et al.  Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. , 1997, The Biochemical journal.

[42]  R. Davis,et al.  Cybrids in Alzheimer's disease: A cellular model of the disease? , 1997, Neurology.

[43]  E. Hirsch,et al.  Annonacin, a Natural Mitochondrial Complex I Inhibitor, Causes Tau Pathology in Cultured Neurons , 2007, The Journal of Neuroscience.

[44]  M. Haan.  Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease , 2006, Nature Clinical Practice Neurology.

[45]  A. Nunomura,et al.  Oxidative Damage Is the Earliest Event in Alzheimer Disease , 2001, Journal of neuropathology and experimental neurology.

[46]  M. King,et al.  Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. , 1989, Science.

[47]  T. Bates,et al.  β‐Amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria , 1999, FEBS letters.

[48]  F. Gabreëls,et al.  Progressive poliodystrophy (alpers') disease) with a defect in cytochromeaa3 in muscle: a report of two unrelated patients , 1983, Clinical Neurology and Neurosurgery.

[49]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[50]  D. Galati,et al.  Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction , 2006, The Journal of Neuroscience.

[51]  I Litvan,et al.  Association of an extended haplotype in the tau gene with progressive supranuclear palsy. , 1999, Human molecular genetics.

[52]  J. Mott,et al.  Mitochondrial DNA mutations activate programmed cell survival in the mouse heart. , 2005, American journal of physiology. Heart and circulatory physiology.

[53]  Robert B. Petersen,et al.  Mitochondrial abnormalities in Alzheimer disease , 2000, Neurobiology of Aging.

[54]  R. Swerdlow,et al.  Functional mitochondria are required for amyloid β‐mediated neurotoxicity , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[55]  P. Vandenabeele,et al.  Toxic proteins released from mitochondria in cell death , 2004, Oncogene.

[56]  R. Hresko,et al.  mTOR·RICTOR Is the Ser473 Kinase for Akt/Protein Kinase B in 3T3-L1 Adipocytes* , 2005, Journal of Biological Chemistry.

[57]  John X. Morris,et al.  Increased risk of dementia in mothers of Alzheimer's disease cases , 1996, Neurology.

[58]  E. Sohar,et al.  Incidence and origin of non-systemic microdeposits of amyloid , 1967, Journal of clinical pathology.

[59]  Kiyofumi Yamada,et al.  Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer's disease. , 2005, Journal of pharmacological sciences.

[60]  X. Estivill,et al.  Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging. , 1997, Brain research. Molecular brain research.

[61]  A. Smith,et al.  Cell cycle markers in the hippocampus in Alzheimer’s disease , 1997, Acta Neuropathologica.

[62]  A Hofman,et al.  Diabetes mellitus and the risk of dementia , 1999, Neurology.

[63]  R. Swerdlow,et al.  Cyclosporin A increases resting mitochondrial membrane potential in SY5Y cells and reverses the depressed mitochondrial membrane potential of Alzheimer's disease cybrids. , 1998, Biochemical and biophysical research communications.

[64]  Wolfgang Härtig,et al.  Reversible Paired Helical Filament-Like Phosphorylation of Tau Is an Adaptive Process Associated with Neuronal Plasticity in Hibernating Animals , 2003, The Journal of Neuroscience.

[65]  G. Johnson,et al.  Tau protein in normal and Alzheimer's disease brain: an update. , 1999, Journal of Alzheimer's disease : JAD.

[66]  Rebecca F. Halperin,et al.  Quantitation of heteroplasmy of mtDNA sequence variants identified in a population of AD patients and controls by array-based resequencing. , 2006, Mitochondrion.

[67]  William M. Mauck,et al.  Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice , 2004, Journal of neurochemistry.

[68]  R. Swerdlow,et al.  A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. , 2004, Medical hypotheses.

[69]  S. Fujita,et al.  Starvation induces tau hyperphosphorylation in mouse brain: implications for Alzheimer's disease , 1999, FEBS letters.

[70]  Michela Gallagher,et al.  A specific amyloid-beta protein assembly in the brain impairs memory. , 2006, Nature.

[71]  G. Šimić,et al.  Mitochondria morphology and DNA content upon sublethal exposure to beta-amyloid(1-42) peptide. , 2008, Collegium antropologicum.

[72]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[73]  R. Swerdlow,et al.  Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer's disease worsen with passage in culture , 2004, Neurobiology of Disease.

[74]  Tracy L. Niedzielko,et al.  Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment. , 2006, Mitochondrion.

[75]  C. Oliveira,et al.  Mitochondrial function impairment induced by amyloid β‐peptide on PC12 cells , 1998 .

[76]  R. Black,et al.  Induction of Alzheimer antigens by an uncoupler of oxidative phosphorylation. , 1990, Archives of Neurology.

[77]  C. Haass,et al.  Protofibrils, the unifying toxic molecule of neurodegenerative disorders? , 2001, Nature Neuroscience.

[78]  D. Sabatini,et al.  Growing roles for the mTOR pathway. , 2005, Current opinion in cell biology.

[79]  Hyoung-Gon Lee,et al.  Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. , 2007, Biochimica et biophysica acta.

[80]  P. Westermark,et al.  Senile amyloidosis: a protean manifestation of the aging process. , 1980, Journal of clinical pathology.

[81]  J. Quinn,et al.  Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. , 2004, Human molecular genetics.

[82]  M. Gallagher,et al.  A specific amyloid-β protein assembly in the brain impairs memory , 2006, Nature.

[83]  K. Herrup,et al.  Re-expression of cell cycle proteins induces neuronal cell death during Alzheimer's disease. , 2002, Journal of Alzheimer's disease : JAD.

[84]  X. Chen,et al.  Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease , 2005 .

[85]  H. Anandatheerthavarada,et al.  Amyloid Precursor Protein and Mitochondrial Dysfunction in Alzheimer's Disease , 2007, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[86]  Brian J Cummings,et al.  Immunohistochemical evidence for apoptosis in Alzheimer's disease. , 1994, Neuroreport.

[87]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[88]  C. Masters,et al.  Copper-Dependent Inhibition of Human Cytochrome c Oxidase by a Dimeric Conformer of Amyloid-β1-42 , 2005, The Journal of Neuroscience.

[89]  S. Kish,et al.  Mitochondria in Alzheimer's disease. , 2002, International review of neurobiology.

[90]  J. Nobrega,et al.  Brain Cytochrome Oxidase in Alzheimer's Disease , 1992, Journal of neurochemistry.

[91]  Seth Love,et al.  Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial , 2008, The Lancet.

[92]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.

[93]  W. Parker,et al.  Cytochrome Oxidase Deficiency in Alzheimer's Disease a , 1991, Annals of the New York Academy of Sciences.

[94]  H. Fung,et al.  Untangling the tau gene association with neurodegenerative disorders. , 2006, Human molecular genetics.

[95]  R. Swerdlow.  Treating neurodegeneration by modifying mitochondria: potential solutions to a "complex" problem. , 2007, Antioxidants & redox signaling.

[96]  William M. Mauck,et al.  Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson’s disease , 2004, Neurobiology of Aging.

[97]  V. Álvarez,et al.  Mitochondrial transcription factor A (TFAM) gene variation and risk of late-onset Alzheimer's disease. , 2008, Journal of Alzheimer's disease : JAD.

[98]  M. Beal,et al.  High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. , 2002, Human molecular genetics.

[99]  I. Santana,et al.  Mitochondria dysfunction of Alzheimer's disease cybrids enhances Aβ toxicity , 2004, Journal of neurochemistry.

[100]  T. Finkel,et al.  Mitochondrial signaling, TOR, and life span , 2006, Biological chemistry.

[101]  R. Swerdlow.  Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies , 2007, Journal of neuroscience research.

[102]  B. Tang,et al.  Widespread γ-secretase activity in the cell, but do we need it at the mitochondria? , 2005 .

[103]  C. Pereira,et al.  Mitochondrial function impairment induced by amyloid beta-peptide on PC12 cells. , 1998, Neuroreport.

[104]  J. Quinn,et al.  Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. , 2006, Human molecular genetics.

[105]  W. Markesbery,et al.  Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[106]  J C Mazziotta,et al.  Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. , 1995, JAMA.

[107]  福家 聡,et al.  DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice , 2008 .

[108]  M. Smith,et al.  Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. , 1997, The American journal of pathology.

[109]  G. J. Colurso,et al.  Quantitative assessment of DNA fragmentation and beta-amyloid deposition in insular cortex and midfrontal gyrus from patients with Alzheimer's disease. , 2003, Life sciences.

[110]  R. Swerdlow,et al.  Abnormal Mitochondrial Morphology in Sporadic Parkinson's and Alzheimer's Disease Cybrid Cell Lines , 2000, Experimental Neurology.

[111]  R. Swerdlow,et al.  Pathogenesis of Alzheimer’s disease , 2007, Clinical interventions in aging.

[112]  M. Beal,et al.  Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[113]  P. Reddy,et al.  P3-291 Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage , 2004, Neurobiology of Aging.

[114]  P. Matsudaira,et al.  Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. , 1994, The Journal of biological chemistry.

[115]  M. Robin,et al.  Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells , 2003, The Journal of cell biology.

[116]  G. Schellenberg,et al.  Multiple SNPs within and surrounding the apolipoprotein E gene influence cerebrospinal fluid apolipoprotein E protein levels. , 2008, Journal of Alzheimer's disease : JAD.

[117]  T. Arendt,et al.  Activated Mitogenic Signaling Induces a Process of Dedifferentiation in Alzheimer's Disease That Eventually Results in Cell Death , 2000, Annals of the New York Academy of Sciences.

[118]  A. Navarro,et al.  The mitochondrial energy transduction system and the aging process. , 2007, American journal of physiology. Cell physiology.

[119]  R. Bhat,et al.  GSK3β Signalling: Casting a Wide Net in Alzheimer’s Disease , 2002, Neurosignals.

[120]  T. Arendt,et al.  Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons – implications for Alzheimer's disease , 2007, The European journal of neuroscience.

[121]  D. Bredesen,et al.  Correction for Galvan et al., Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664 , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[122]  J. Parks,et al.  Cytochrome C Oxidase in Alzheimer's Disease Brain , 1995, Neurology.

[123]  Stavros J. Baloyannis,et al.  Mitochondrial alterations in Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[124]  J. Bohl,et al.  Senile amyloidosis: Principles of localization in a heterogeneous form of amyloidosis , 1983, Virchows Archiv. B, Cell pathology including molecular pathology.

[125]  R. Nitsch,et al.  Possible association of mitochondrial transcription factor A (TFAM) genotype with sporadic Alzheimer disease , 2004, Neuroscience Letters.

[126]  R. Swerdlow,et al.  Alzheimer's disease cybrids replicate beta-amyloid abnormalities through cell death pathways. , 2000, Annals of neurology.

[127]  B. Winblad,et al.  Nicastrin, Presenilin, APH-1, and PEN-2 Form Active γ-Secretase Complexes in Mitochondria* , 2004, Journal of Biological Chemistry.

[128]  C. Cooper,et al.  The inhibition of mitochondrial cytochrome oxidase by the gases carbon monoxide, nitric oxide, hydrogen cyanide and hydrogen sulfide: chemical mechanism and physiological significance , 2008, Journal of bioenergetics and biomembranes.

[129]  R. Swerdlow,et al.  Mitochondria and ubiquitin-proteasomal system interplay: relevance to Parkinson's disease. , 2008, Free radical biology & medicine.

[130]  P. Francis,et al.  The effects of perturbed energy metabolism on the processing of amyloid precursor protein in PC12 cells , 1998, Journal of Neural Transmission.

[131]  M. Beal,et al.  Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. , 1994, Genomics.

[132]  J. Hardy,et al.  Alzheimer's disease: the amyloid cascade hypothesis. , 1992, Science.

[133]  Jeffrey A. James,et al.  Frequent amyloid deposition without significant cognitive impairment among the elderly. , 2008, Archives of neurology.

[134]  R. Jope,et al.  The multifaceted roles of glycogen synthase kinase 3β in cellular signaling , 2001, Progress in Neurobiology.

[135]  T. D. Pugh,et al.  Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging , 2005, Science.

[136]  B. Winblad,et al.  The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae , 2008, Proceedings of the National Academy of Sciences.

[137]  Shaomin Li,et al.  Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory , 2008, Nature Medicine.