1Department of Pharmacology, University of Frankfurt/M, Biocenter, D-60438 Frankfurt, Germany 2Deparment of Molecular and Clinical Pharmacy, University of Erlangen, D-91058 Erlangen, Germany 3Department of Nutricional Sciences, University of Giessen, D-35392 Giessen, Germany
Dimebon (latrepirdine), an old antihistaminic drug, showed divergent results in two large clinical trials in Alzheimer disease (AD), which according to our review might be related to the specific pharmacological properties of the drug and the different patient populations included in both studies. Out of the many pharmacological effects of Dimebon, improvement of impaired mitochondrial function seeems to be most relevant for the substantial effects on cognition and behaviour reported in one of the studies, as these effects are already present at the low concentrations of dimebon measured in plasma and tissues of patients and experimental animals. Since impaired mitochondrial function seems to be the major driving force for the progression of the clinical symptoms and since most of the clinical benefits of dimebon originate from an effect on the symptomatic deterioration, mitochondrial improvement can also explain the lack of efficacy of this drug in another clinical trial where symptoms of the patiets remained stable for the time of the study. Accordingly, it seems worthwhile to reevaluate the clinical data to proof that clinical response is correlated with high levels of Neuropsychiatric Symptoms as these show a good relationship to the individual speed of symptomatic decline in AD patients related to mitochondrial dysfunction.
Eckert Schamim H,Gaca Janett,Kolesova Nathalie, et al. Mitochondrial Pharmacology of Dimebon (Latrepirdine) Calls for a New Look at its Possible Therapeutic Potential in Alzheimer’s Disease[J]. Aging and disease,
2018, 9(4): 729-744.
Figure 1. Effects on respiratory activity (adapted and mofified from Eckert et al. )
HEKsw cells were incubated for 6 h with dimebon (0.1 µM) and oxygen consumption (respiration [pmolx s-1 x mill-1 cells]) was measured in different mitochondrial stages by injecting several substrates and inhibitors in an Oxygraph 2k (Innsbruck, Austria). CIOXPHOS, CI dependent oxidative phosphorylationdetermined with complex I related substrates glutamate, malate and ADP; CI+IIOXPHOS, oxidative phosphorylation providing CI and CII substrates by addition of succinate; CI+IIETS, non-coupled respiration with CI and CII substrates, is considered as maximum capacity of the ETS by uncoupling with carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP, injected stepwise up to 1-1.5 µM); CIIETS, non-coupled CII dependent respirationby subsequent inhibition of complex I with rotenone; CIVETS, non-coupled respiration with CIV substrates, applying tetramethylphenylenediamine (TMPD) as an artificial substrate and ascorbate to keep TMPD in the reduced state. Values represent the means ± SEM from n = 6-9 experiments per protocol, Two-way ANOVA with Bonferroni post-tests, *p<0.05, **p<0.01, ***p<0.001.
Figure 2. Effects on mitochondrial morphology (adapted and modified from Eckert et al.  Müller et al. (37), Eckert (38))
HEK-cells harboring the Swedish mutation in the APP gene (HEKsw) and control cells (HEKut) cells were incubated with dimebon (0.1 µM) for 6 h. (A) For the determination of mitochondrial length, organells were labeled with Mito Tracker CMXRos, fixed with PFA. Mitochondrial lengths were quantified using Image J and classified in punctuated, truncated, tubular, and elongated mitochondria. Data represent the means ± SEM with at least 100 measured mitochondria per experiment, n = 8-9, Two-way ANOVA with Bonferroni post-tests, **p<0.01, ***p<0.001. (B, C) Effects of dimebon on expression levels of fission and fusion marker. Marker proteins for fission dynamin related protein1 (Drp) and fission 1 related protein (Fis), as well as markers for mitochondrial fusion protein 1 (Mfn) and optic atrophie-1 (Opa) were measured using Western Blot analysis, after electrophoretic separation and using specific antibodies. Cellular location of the proteins in the cytosolic fraction as well as in inner (IMM) and outer (OMM) mitochondrial membranes is indicated. Data were normalized to HEKut (100%) and represent the means ± SEM, n = 8-9, Two-way ANOVA with Bonferroni post-tests, *p<0,05, **p<0,01, ***p<0,001 vs. ctl; #p<0,05, ##p<0,01 vs. HEKsw. (D) Representative Western Blots.
Figure 3. Effects on mitochondrial membrane composition (adapted and modified from Müller et al. , Eckert )
Cells were incubated with 0,1 μM dimebon (Dim) for 6 h. (A) In HEK control cells (HEKut) and (B) HEK-cells harboring the Swedish mutation in the APP gene (HEKsw), marker proteins for the inner (IMM) and the outer mitochondrial membrane (OMM), were measured in total homogenates, using Western Blot analysis after electrophoretic separation and using specific antibodies against translocator proteins of the inner (TIMM50) and outer (TOMM22) mitochondrial membrane, respectively. Data were normalized to HEKut (100% in A) and HEKsw (100% in B), respectively. Data represent the means ± SEM, n = 6, Two-way ANOVA with Bonferroni post-tests, *p<0,05, ***p<0,001. (C) Representative Western Blots.
Figure 4. Effects on mitophagy (adapted and modified from Müller et al., Eckert )
(A) Control cells (HEKut) and (C) HEK-cells harboring the Swedish mutation in the APP gene (HEKsw) an were incubated with 0,1 µM dimebon (Dim) for 6 h. Autophagy marker proteins for the cytosol (LC3-I) and autophagosomal membranes (LC3-II) as well as the transcription marker peroxisome proliferation-activated receptor gamma coactivator 1-alpha (PGC), were measured using western blot analysis after electrophoretic separation and using specific antibodies in total cellular homogenates. (B & D) A low LC3-I/LC3-II ratio indicates high degree of mitophagy. Data were normalized to HEKut (100%) and represent the means ± SEM, n = 8-9, Two-way ANOVA with Bonferroni post-tests, *p<0,05, **p<0,01 vs. HEKut ctr; #p<0,05 vs. HEKsw ctl. (E) Representative Western Blots.
Figure 5. Effects on structure and function of the mitochondrial permeability transition pore (mPTP) (adapted and modified from Müller et al. )
(A) HEKswcells were incubated with 0,1 µM dimebon (Dim) for 6 h, mPTP marker proteins of the outer mitochondrial membranes (OMM), voltage-depended anion channel (VDAC) and peripheral benzodiazepine receptor (PBR), were examined using western blot analysis after electrophoretic separation and using specific antibodies in total homogenates. Data were normalized to HEKut (100%) and represent the means ± SEM, n = 8-9, Two-way ANOVA with Bonferroni post-tests, **p<0,01, *p<0,05, ***p<0,001 vs. HEKut ctl; #p<0,05 vs. HEKsw ctl. (B) Representative Western Blots. In HEKsw cells, dimebon dramatically restored the increased expression levels of these mPTP markers (Fig 5 A). (C) Exemplary graph of a measurement of light scattering which is equivalent to mitochondrial swelling; Ca2+: inductor of physiological extent of mitochondrial swelling; Ala: Alamethicin [3.2 mg/mL], inductor of maximal mitochondrial swelling. (D) Swelling of isolated mitochondria from female NMRI mice challenged with calcium (Ca2+, 2 mmol/mg protein) and simultaneously incubated with cyclosporin A, a known inhibitor of mitochondrial swelling (CsA, 1 µM) and dimebon (0.1 µM; statistics were calculated against calcium insult; (; n=5-8; mean ± SEM; p*<0.05; p**<0.01; p***<0.001
Bachurin S, Bukatina E, Lermontova N, Tkachenko S, Afanasiev A, Grigoriev V, Grigorieva I, Ivanov Y, Sablin S, Zefirov N (2001). Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci, 939:425-35.
Sachdeva D, Burns A (2011). Dimebolin in dementia. CNS Neurosci Ther, 17(3):199-205.
Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D; dimebon investigators (2008). Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet, 372(9634):207-15.
Kieburtz K, McDermott MP, Voss TS, Corey-Bloom J, Deuel LM, Dorsey ER, Factor S, Geschwind MD, Hodgeman K, Kayson E, Noonberg S, Pourfar M, Rabinowitz K, Ravina B, Sanchez-Ramos J, Seely L, Walker F, Feigin A; Huntington Disease Study Group DIMOND Investigators (2010). A randomized, placebo-controlled trial of latrepirdine in Huntington disease. Arch Neurol, 67(2):154-60.
HORIZON Investigators of the Huntington Study Group and European Huntington’s Disease Network (2013). A randomized, double-blind, placebo-controlled study of latrepirdine in patients with mild to moderate Huntington disease. JAMA Neurol, 70(1):25-33.
Pfizer and Medivation annonce results from two phase 3 studies in Dimebon (latrepirdine*) Alzheimer’s Disease Clinical Development Program. Medivation March 2010,http://investors.medivation.com/releasedetail.Cfm?ReleaseID=448818.
Bharadwaj PR, Bates KA, Porter T, Teimouri E, Perry G, Steele JW, Gandy S, Groth D, Martins RN, Verdile G (2013). Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer’s and other neurodegenerative diseases. Transl Psychiatry, 3: e332.
Cano-Cuenca N, Solís-García del Pozo JE, Jordán J (2014). Evidence for the efficacy of latrepirdine (Dimebon) treatment for improvement of cognitive function: a meta-analysis. J Alzheimers Dis, 358(1):155-64.
Chau S, Herrmann N, Ruthirakuhan MT, Chen JJ, Lanctôt KL (2015).Latrepirdine for Alzheimer’s disease. Cochrane Database Syst Rev,(4): CD009524.
Ustyugov A, Shevtsova E, Bachurin S (2015). Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine). Mol Neurobiol, 52(2):970-8.
Sabbagh MN, Shill HA (2010). Latrepirdine, a potential novel treatment for Alzheimer’s disease and Huntington’s chorea. Curr Opin Investig Drugs, 11(1):80-91.5
Giorgetti M, Gibbons JA, Bernales S, Alfaro IE, Drieu La Rochelle C, Cremers T, Altar CA, Wronski R, Hutter-Paier B, Protter AA (2010). Cognition-enhancing properties of Dimebon in a rat novel object recognition task are unlikely to be associated with acetylcholinesterase inhibition or N-methyl-D-aspartate receptor antagonism. J Pharmacol Exp Ther, 333(3): 748-57.
Wang J, Ferruzzi MG, Varghese M, Qian X, Cheng A, Xie M, Zhao W, Ho L, Pasinetti GM (2011). Preclinical study of dimebon on β-amyloid-mediated neuropathology in Alzheimer’s disease. Mol Neurodegener, 6(1):7.
Zhang S, Hedskog L, Petersen CA, Winblad B, Ankarcrona M (2010). Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death. J Alzheimers Dis, 21(2):389-402.
Chew ML, Mordenti J, Yeah T, Ranade G, Qiu R, Fang J, Liang Y, Corrigan B (2016). Minimization of CYP2D6 Polymorphic Differences and Improved Bioavailability via Transdermal Administration: Latrepirdine Example. Pharm Res, 33(8):1873-80.
Wu J, Li Q, Bezprozvanny I (2008). Evaluation of Dimebon in cellular model of Huntington’s disease. Mol Neurodegener, 3:15.
Bezprozvanny I (2010). The rise and fall of Dimebon. Drug News Perspect, 23(8):518-23.
Lermontova NN, Lukoyanov NV, Serkova TP, Lukoyanova EA, Bachurin SO (2000). Dimebon improves learning in animals with experimental Alzheimer’s disease. Bull Exp Biol Med, 129(6):544-6.
Grigorev VV, Dranyi OA, Bachurin SO (2003). Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med, 136(5):474-7.
Schaffhauser H, Mathiasen JR, Dicamillo A, Huffman MJ, Lu LD, McKenna BA, Qian J, Marino MJ (2009). Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. Biochem Pharmacol, 78(8):1035-42.
Ferrero H, Solas M, Francis PT, Ramirez MJ (2017). Serotonin 5-HT6 Receptor Antagonists in Alzheimer’s Disease: Therapeutic Rationale and Current Development Status. CNS Drugs, 31(1):19-32.
Steele JW, Lachenmayer ML, Ju S, et al (2013). Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer’s mouse model. Mol Psychiatry, 18(8): 889-97.
Vignisse J, Steinbusch HW, Bolkunov A, et al (2011). Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice. Prog Neuropsychopharmacol Biol Psychiatry, 35(2): 510-22.
Cowley TR, González-Reyes RE, Richardson JC, Virley D, Upton N, Lynch MA (2013). The age-related gliosis and accompanying deficit in spatial learning are unaffected by dimebon. Neurochem Res, 38(6):1190-5.
Webster SJ, Wilson CA, Lee CH, Mohler EG, Terry AV Jr, Buccafusco JJ (2011). The acute effects of dimebolin, a potential Alzheimer’s disease treatment, on working memory in rhesus monkeys. Br J Pharmacol, 164(3): 970-8.
Malatynska E, Steinbusch HW, Redkozubova O, Bolkunov A, Kubatiev A, Yeritsyan NB, Vignisse J, Bachurin S, Strekalova T (2012). Anhedonic-like traits and lack of affective deficits in 18-month-old C57BL/6 mice: Implications for modeling elderly depression. Exp Gerontol, 47(8): 552-64.
Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO (2003). Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci, 993:334-44
Perez SE, Nadeem M, Sadleir KR, Matras J, Kelley CM, Counts SE, Vassar R, Mufson EJ (2012). Dimebon alters hippocampal amyloid pathology in 3xTg-AD mice. Int J Physiol Pathophysiol Pharmacol, 4(3):115-27.
Egea J, Romero A, Parada E, León R, Dal-Cim T, López MG (2014). Neuroprotective effect of dimebon against ischemic neuronal damage. Neuroscience. 267:11-21.
Porter T, Bharadwaj P, Groth D, Paxman A, Laws SM, Martins RN, Verdile G (2016). The Effects of Latrepirdine on Amyloid-β Aggregation and Toxicity. J Alzheimers Dis, 50(3): 895-905.
Khritankova IV, Kukharskiy MS, Lytkina OA, Bachurin SO, Shorning BY (2012). Dimebon activates autophagosome components in human neuroblastoma SH-SY5Y cells. Dokl Biochem Biophys, 446:251-3.
Steele JW, Ju S, Lachenmayer ML, Liken J, et al (2013). Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain. Mol Psychiatry, 18(8):882-8.
Steele JW, Gandy S (2013). Latrepirdine (Dimebon®), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model. Autophagy, 9(4): 617-8.
Naga KK, Geddes JW (2011). Dimebon inhibits calcium-induced swelling of rat brain mitochondria but does not alter calcium retention or cytochrome C release. Neuromolecular Med, 13(1): 31-6.
Eckert SH, Eckmann J, Renner K, Eckert GP, Leuner K, Muller WE (2012). Dimebon ameliorates amyloid-β induced impairments of mitochondrial form and function. J Alzheimers Dis, 31(1): 21-32.
Müller WE, Eckert SH, Leuner K (2012). Mitochondrial quality control: Effects of Dimebon on mitophagy and apoptosis. Neuroscience abstract no. 620.04.
Eckert SH, (2017). Pharmacological modulation of mitochondrial dysfunction gy Dimebon and Olesoxim in cellular and murine models of Alzheimer’s disease. PhD dissertation, Faculty of Biochemistry, Chemistry, and Pharmacy, Goethe-University, Frankfurt.
Stockburger C, Gold VA, Pallas T, et al (2014). A cell model for the initial phase of sporadic Alzheimer’s disease. J Alzheimers Dis, 42(2):395-411.
Stockburger C, Miano D, Bäumlisgerger M, Pallas T, Arrey TN, Karas M, Friedland K, Müller WE (2016a). A mitochondrial role of SY2a protein in aging and Alzheimer’s disease: Studies with levetiracetam. J Alzmeimers Dis 50: 201-215
Stockburger C, Miano D, Pallas T, Friedland K, Müller WE (2016b). Enhanced Neuroplasticity by the Metabolic Enhancer Piracetam Associated with Improved Mitochondrial Dynamics and Altered Permeability Transition Pore Function. Neural Plast, 2016: 8075903.
Hagl S, Grewal R, Ciobanu I, Helal A, Khayyal MT, Muller WE, Eckert GP (2015). Rice bran extract compensates mitochondrial dysfunction in a cellular model of early Alzheimer’s disease. J Alzheimers Dis, 43(3): 927-38.
Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016). MH84: A Novel γ-Secretase Modulator/PPARγ Agonist--Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer’s Disease. Neurochem Res, 41(1-2): 231-42.
Keil U, Bonert A, Marques CA, Scherping I, Weyermann J, Strosznajder JB, Müller-Spahn F, Haass C, Czech C, Pradier L, Müller WE, Eckert A (2004).Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem, 279(48): 50310-20.
Leuner K, Schütt T, Kurz C, et al (2012). Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation. Antioxid Redox Signal, 16(12):1421-33.
Hauptmann S, Scherping I, Dröse S, Brandt U, Schulz KL, Jendrach M, Leuner K, Eckert A, Müller WE (2009). Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging, 30(10):1574-86.
Swerdlow RH, Burns JM, Khan SM (2014). The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta, 1842(8): 1219-31.
Friedland-Leuner K, Stockburger C, Denzer I, Eckert GP, Müller WE (2014). Mitochondrial dysfunction: cause and consequence of Alzheimer’s disease. Prog Mol Biol Transl Sci, 127: 183-210.
Chakrabarti S, Khemka VK, Banerjee A, Chatterjee G, Ganguly A, Biswas A (2015). Metabolic Risk Factors of Sporadic Alzheimer’s Disease: Implications in the Pathology, Pathogenesis and Treatment. Aging Dis, 6(4): 282-99.
Reddy PH, Manczak M, Mao P, Calkins MJ, Reddy AP, Shirendeb U (2010). Amyloid-beta and mitochondria in aging and Alzheimer’s disease: implications for synaptic damage and cognitive decline. J Alzheimers Dis, 20 Suppl 2: S499-512.
Mattson MP (2007). Mitochondrialregulation of neuronal plasticity. Neurochem Res, 32(4-5):707-15.
Chakrabarti S, Sinha M, Thakurta IG, Banerjee P, Chattopadhyay M (2013). Oxidative stress and amyloid beta toxicity in Alzheimer’s disease: intervention in a complex relationship by antioxidants. Curr Med Chem, 20(37):4648-64.
Müller WE, Eckert A, Eckert GP, et al (2017). Therapeutic efficacy of the Ginkgo special extract EGb761 within the framework of the mitochondrial cascade hypothesis of Alzheimer’s disease. W J Biol Psychiat, May 2: 1-17
Müller WE, Eckert A, Kurz C, Eckert GP, Leuner K (2010). Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer’s disease--therapeutic aspects. Mol Neurobiol, 41(2-3):159-71.
Leuner K, Hauptmann S, Abdel-Kader R, et al (2007). Mitochondrial dysfunction: the first domino in brain aging and Alzheimer’s disease? Antioxid Redox Signal, 9(10):1659-75.
Onyango IG, Dennis J, Khan SM (2016). Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies. Aging Dis, 7(2):201-14.
Andreux PA, Houtkooper RH, Auwerx J (2013). Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Discov, 12(6):465-83.
Kumar A, Singh A (2015). A review on mitochondrial restorative mechanism of antioxidants in Alzheimer’s disease and other neurological conditions. FrontPharmacol, 24:206.
Eckert GP, Renner K, Eckert SH, et al (2012). Mitochondrial dysfunction--a pharmacological target in Alzheimer’s disease. Mol Neurobiol, 46(1):136-50.
Day M, Chandran P, Luo F, et al (2011). Latrepirdine increases cerebral glucose utilization in aged mice as measured by [18F]-fluorodeoxyglucose positron emission tomography. Neuroscience, 189: 299-304.
Du H, Guo L, Yan SS (2012). Synaptic mitochondrial pathology in Alzheimer’s disease. Antioxid Redox Signal, 16(12):1467-75.
Kurz C, Ungerer I, Lipka U, Kirr S, Schütt T, Eckert A, Leuner K, Müller WE (2010).The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by beta-amyloid peptide. Br J Pharmacol, 160(2):246-57.
Bernales S, Chacon M, Alarcon R, Guerrero J, Protter AA (2009). Dimebon induces neurite outgrowth with hippocampal, spinal, and cortical neurons. Neurology, 72(11) Abs. P08.079.
Page M, Pacico N, Ourtioualous S, Deprez T, Koshibu K (2015). Procognitive Compounds Promote Neurite Outgrowth. Pharmacology, 96(3-4):131-6.
Eckmann J, Eckert SH, Leuner K, Muller WE, Eckert GP (2013). Mitochondria: mitochondrial membranes in brain ageing and neurodegeneration. Int J Biochem Cell Biol, 45(1):76-80.
Vasiljev A, Ahting U, Nargang FE, et al (2004). Reconstituted TOM core complex and Tim9/Tim10 complex of mitochondria are sufficient for translocation of the ADP/ATP carrier across membranes. Mol Biol Cell, 15(3):1445-58.
Sirrenberg C, Bauer MF, Guiard B, Neupert W, Brunner M (1996). Import of carrier proteins into the mitochondrial inner membrane mediated by Tim22. Nature, 384(6609):582-5.
Dekker PJ, Ryan MT, Brix J, Müller H, Hönlinger A, Pfanner N (1998). Preprotein translocase of the outer mitochondrial membrane: molecular dissection and assembly of the general import pore complex. Mol Cell Biol, 18(11):6515-24.
Rehling P, Wiedemann N, Pfanner N, Truscott KN (2001). The mitochondrial import machinery for preproteins. Crit Rev Biochem Mol Biol, 36(3):291-336.
Voos W, Martin H, Krimmer T, Pfanner N (1999). Mechanisms of protein translocation into mitochondria. Biochim Biophys Acta, 1422(3):235-54.
Scarpulla RC, Vega RB, Kelly DP (2012). Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol Metab, 23(9):459-66.
St-Pierre J, Drori S, Uldry M, et al (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 127(2): 397-408.
Chen H, Chan DC (2009). Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases. Hum Mol Genet, 18(R2): R169-76.
Patel PK, Shirihai O, Huang KC (2013). Optimal dynamics for quality control in spatially distributed mitochondrial networks. PLoS Comput Biol, 9(7): e1003108.
Cai Q, Tammineni P (2016). Mitochondrial Aspects of Synaptic Dysfunction in Alzheimer’s Disease. J. Alzheimers Dis, in press.
Benard G, Rossignol R (2008). Ultrastructure of the mitochondrion and its bearing on function and bioenergetics. Antioxid Redox Signal, 10(8):1313-42.
Onyango IG, Dennis J, Khan SM (2016). Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies. Aging Dis, 7(2): 201-214.
Zhu X, Perry G, Smith MA, Wang X (2013). Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer’s disease. J Alzheimers Dis, 33 Suppl 1:S253-62.
Picard M, Shirihai OS, Gentil BJ, Burelle Y (2013). Mitochondrial morphology transitions and functions: implications for retrograde signaling? Am J Physiol Regul Integr Comp Physiol, 304(6):R393-406.
Bossy-Wetzel E, Barsoum MJ, Godzik A, Schwarzenbacher R, Lipton SA (2003). Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr Opin Cell Biol, 15(6):706-16.
Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwenburgh C (2010). New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci, 123(Pt 15):2533-42.
Jendrach M, Pohl S, Vöth M, Kowald A, Hammerstein P, Bereiter-Hahn J (2005). Morpho-dynamic changes of mitochondria during ageing of human endothelial cells. Mech Ageing Dev, 126(6-7):813-21.
Twig G, Shirihai OS (2011). The interplay between mitochondrial dynamics and mitophagy. Antioxid Redox Signal, 14(10):1939-51.
Barnett A, Brewer GJ (2011). Autophagy in aging and Alzheimer’s disease: pathologic or protective? J Alzheimers Dis, 25(3):385-94.
Batlevi Y, La Spada AR (2011). Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging. Neurobiol Dis, 43(1):46-51.
Lionaki E, Markaki M, Palikaras K, Tavernarakis N (2015).Mitochondria, autophagy and age-associated neurodegenerative diseases: New insights into a complex interplay. Biochim Biophys Acta, 1847(11): 1412-23.
Santos RX, Correia SC, Wang X, et al (2010). A synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer’sdisease. J Alzheimers Dis, 20 Suppl 2:S401-12.
Tanida I (2011). Autophagosome formation and molecular mechanism of autophagy. Antioxid Redox Signal, 14(11):2201-14.
Levine B, Kroemer G (2008).Autophagy in the pathogenesis of disease. Cell, 132(1):27-42.
Bachurin SO, Shelkovnikova TA, Ustyugov AA, Peters O, Khritankova I, Afanasieva MA, Tarasova TV, Alentov II, Buchman VL, Ninkina NN (2012). Dimebon slows progression of proteinopathy in γ-synuclein transgenic mice. Neurotox Res, 22(1):33-42.
Palikaras K, Tavernarakis N (2012). Mitophagy in neurodegeneration and aging. Front Genet, 3:297.
Azarashvili T, Stricker R, Reiser G (2010). The mitochondria permeability transition pore complex in the brain with interacting proteins - promising targets for protection in neurodegenerative diseases. Biol Chem, 391(6): 619-29.
Rasola A, Bernardi P (2007). The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis, 12(5):815-33.
Zorov DB, Juhaszova M, Yaniv Y, Nuss HB, Wang S, Sollott SJ (2009). Regulation and pharmacology of the mitochondrial permeability transition pore. Cardiovasc Res. 83(2):213-25.
Gazaryan IG, Brown AM (2007).Intersection between mitochondrial permeability pores and mitochondrial fusion/fission. Neurochem Res, 32(4-5):917-29.
Peixoto PM, Dejean LM, Kinnally KW (2012). The therapeutic potential of mitochondrial channels in cancer, ischemia-reperfusion injury, and neurodegeneration. Mitochondrion, 12(1):14-23.
Shoshan-Barmatz V, Ben-Hail D (2012). VDAC, a multi-functional mitochondrial protein as a pharmacological target. Mitochondrion, 12(1):24-34.
Hansson MJ, Mattiasson G, Månsson R, et al (2004). The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J Bioenerg Biomembr, 36(4):407-13.
Herrup K (2015). The case for rejecting the amyloid cascade hypothesis. Nat Neurosci, 18(6):794-9.
Iqbal K, Liu F, Gong CX (2014). Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles. Biochem Pharmacol, 88(4):631-9.
Jack CR Jr, Knopman DS, Jagust WJ, et al (2013). Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol, 12(2):207-16.
Jack CR Jr, Wiste HJ, Weigand SD, et al (2014). Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: a cross-sectional study. Lancet Neurol, 13(10):997-1005.
Sperling RA, Aisen PS, Beckett LA, et al (2011). Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement, 7(3):280-92.
Moreira PI, Zhu X, Wang X, Lee HG, Nunomura A, Petersen RB, Perry G, Smith MA (2010). Mitochondria: a therapeutic target in neurodegeneration.Biochim Biophys Acta. 1802(1):212-20.
Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT (1998). A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology, 50(1):136-45.
Aalten P, Verhey FR, Boziki M, et al (2008). Consistency of neuropsychiatric syndromes across dementias: results from the European Alzheimer Disease Consortium. Part II. Dement Geriatr Cogn Disord, 25(1):1-8.
Aalten P, Verhey FR, Boziki M, et al (2007). Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: part I. Dement Geriatr Cogn Disord, 24(6):457-63.
Apostolova LG, Cummings JL (2008). Neuropsychiatric manifestations in mild cognitive impairment: a systematic review of the literature.Dement Geriatr Cogn Disord, 25(2):115-26.
Steinberg M, Shao H, Zandi P, Lyketsos CG, Welsh-Bohmer KA, Norton MC, Breitner JC, Steffens DC, Tschanz JT; Cache County Investigators (2008). Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry, 23(2):170-7.
Di Iulio F, Palmer K, Blundo C, Casini AR, Gianni W, Caltagirone C, Spalletta G (2010). Occurrence of neuropsychiatric symptoms and psychiatric disorders in mild Alzheimer’s disease and mild cognitive impairment subtypes. Int Psychogeriatr, 22(4):629-40.
Herrmann N, Harimoto T, Balshaw R, Lanctôt KL; Canadian Outcomes Study in Dementia (COSID) Investigators (2015). Risk Factors for Progression of Alzheimer Disease in a Canadian Population: The Canadian Outcomes Study in Dementia (COSID).Can J Psychiatry, 60(4):189-99.
Petrovic M, Hurt C, Collins D, Burns A, Camus V, Liperoti R, Marriott A, Nobili F, Robert P, Tsolaki M, Vellas B, Verhey F, Byrne EJ (2007). Clustering of behavioural and psychological symptoms in dementia (BPSD): a European Alzheimer’s disease consortium (EADC) study. Acta Clin Belg, 62(6):426-32.
Peters ME, Rosenberg PB, Steinberg M, Norton MC, Welsh-Bohmer KA, Hayden KM, Breitner J, Tschanz JT, Lyketsos CG; Cache County Investigators (2013). Neuropsychiatric symptoms as risk factors for progression from CIND to dementia: the Cache County Study. Am J Geriatr Psychiatry, 21(11):1116-24.
Peters ME, Schwartz S, Han D, Rabins PV, Steinberg M, Tschanz JT, Lyketsos CG (2015). Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s dementia and death: the Cache County Dementia Progression Study. Am J Psychiatry, 172(5):460-5.
Schneider LS, DeKosky ST, Farlow MR, Tariot PN, Hoerr R, Kieser M (2005). A randomized, double-blind, placebo-controlled trial of two doses of Ginkgo biloba extract in dementia of the Alzheimer’s type.Curr Alzheimer Res, 2(5):541-51.
Cerejeira J, Lagarto L, Mukaetova-Ladinska EB (2012). Behavioral and psychological symptoms of dementia. Front Neurol, 3:73.
Meeks TW, Ropacki SA, Jeste DV (2006). The neurobiology of neuropsychiatric syndromes in dementia. Curr Opin Psychiatry, 19(6):581-6.
Morris G, Berk M (2015). The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders, BMC Med, 13:68.
Sultzer DL, Leskin LP, Melrose RJ, et al (2014). Neurobiology of delusions, memory, and insight in Alzheimer disease. Am J Geriatr Psychiatry, 22(11): 1346-55.
Vaváková M, Ďuračková Z, Trebatická J (2015). Markers of Oxidative Stress and Neuroprogression in Depression Disorder. Oxid Med Cell Longev, 2015:898393.