Experimental Neurology 223 (2010) 294–298
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Experimental Neurology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y e x n r
Review
Mitochondrial control of autophagic lysosomal pathway in Alzheimer's disease S.M. Cardoso a,b,c, C.F. Pereira a,b, P.I. Moreira a,d, D.M. Arduino a, A.R. Esteves a, C.R. Oliveira a,b,c,⁎ a
Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal c Institute of Biology – Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal d Institute of Physiology – Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal b
a r t i c l e
i n f o
Article history: Received 6 April 2009 Revised 16 June 2009 Accepted 17 June 2009 Available online 25 June 2009 Keywords: Alzheimer's disease Amyloid β Mitochondria Oxidative stress Macroautophagy
a b s t r a c t When first described by Alois Alzheimer in 1907, AD was seen as a disorder that causes dementia and characterized by two defining neuropathological lesions, later associated with all forms of AD. While the etiology of AD remains largely unclear, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in AD. Mitochondria are exceptionally poised to play a crucial role in neuronal cell survival or death because they are regulators of both energy metabolism and apoptotic pathways. This review is mainly focused in the discussion of evidence suggesting a clear association between mitochondrial dysfunction, autophagy impairment and amyloid-β accumulation in Alzheimer's disease pathophysiology. The knowledge that autophagic insufficiency may compromise the cellular degradation mechanisms that may culminate in the progressive accumulation of dysfunctional mitochondria, aberrant protein aggregates buildup and lysossomal burden shield new insights to the way we address Alzheimer's disease. In line with this knowledge an innovative window for new therapeutic strategies aimed to activate or ameliorate macroautophagy may be opened. © 2009 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . Mitochondrial dysfunction: a key indicator for AD pathology . Mitochondria versus Abeta . . . . . . . . . . . . . . . . . Macroautophagy impairment in AD mediates Abeta production Mitochondrial–lysosomal nexus in AD . . . . . . . . . . . . Concluding remarks. . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Alzheimer disease (AD) is a progressive and fatal disorder of the central nervous system characterized by progressive memory loss, deterioration of cognitive functions and loss of synapses and neurons in the cerebral cortex and hippocampus. Two typical hallmarks of AD are intraneuronal neurofibrillar tangles (NFT) of hyperphosphorylated tau protein and extracellular senile plaques composed of fibrillar Abeta peptide. Abeta is a 40- to 42-amino acid peptide originating from the abnormal proteolysis of the amyloid precursor protein (APP)
⁎ Corresponding author. Center for Neuroscience and Cell Biology and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal. Fax: +351 239 822776. E-mail addresses:
[email protected] (S.M. Cardoso),
[email protected] (C.R. Oliveira). 0014-4886/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2009.06.008
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(Selkoe, 1993). Although fibrillar Abeta has been linked to the pathogenesis of AD for many years, recent studies have suggested a key role for soluble forms of the peptide in neuronal dysfunction (Klein et al., 2004). Studies from our group have reported that these peptides affect the electron transport chain, leading to the impairment of mitochondrial function (Cardoso et al., 2001; Pereira et al., 1999). Alterations of mitochondrial metabolism in AD patients have been well documented in the literature (reviewed in Moreira et al., 2006). Moreover, mitochondrial degeneration was shown to be an early sign of AD pathology appearing before NFT (Hirai et al., 2001). Several studies suggest that altered proteolytic processing of APP is synergistically related with impaired energy metabolism. First, brain glucose metabolism is decreased in cognition-related brain regions of APP mutant mice in association with increased amounts of Abeta (Dodart et al., 1999). Second, hypoxic tolerance is significantly decreased in presymptomatic Abeta APP mutant mice (Buchner et al., 2002). Third,
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caloric restriction protects neurons in experimental models relevant to AD (Mattson, 2003). Finally, impaired energy metabolism can induce amyloidogenic processing of APP, resulting in the accumulation of potentially neurotoxic forms of Abeta (Gabuzda et al., 1994). Taken together, these data suggest that Abeta peptides translocate directly to the mitochondria may be responsible for the impairment of mitochondrial function that occurs in AD, at least for familial cases. The mechanism by which Abeta impairs mitochondrial function seems to involve enhanced reactive oxygen species (ROS) production (Cardoso and Oliveira, 2003), since several enzyme complexes of the respiratory chain are particularly vulnerable to damage by both Abeta and ROS (Cardoso et al., 2001; Pereira et al., 1999). Protein oligomerization and aggregation are key events in agerelated neurodegenerative disorders, causing neuronal disturbances that may include over-activation of macroautophagy. Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. During macroautophagy, an elongated “isolation” membrane sequesters a region of cytoplasm to form a double-membranelimited autophagosome. The sequestered material within autophagosomes is digested by lysosomes upon fusion (autophagolysosomes) (Eskelinen, 2008). Recently, it was demonstrated that autophagy is constitutively active in neurons and is required for survival (Larsen and Sulzer, 2002). It has been described that the autophagosome– lysosome pathway (ALP) is compromised in AD brain and in animal AD models (Nixon et al., 2005; Yu et al., 2005). Neuritic dystrophy correlates with an increase in autophagic vacuoles (AV) induced early in AD before Abeta deposits extracellularly (Yu et al., 2005). It was demonstrated that Abeta peptides are degraded in normal conditions by the lysosome after autophagosome/endosome fusion. Subsequently, autophagosomes and late AV accumulate markedly in dystrophic dendrites, implying an impaired maturation of AV to lysosomes (Nixon, 2007). In this review we will address mitochondria dysfunction as an initial cellular signalling pathway for AD etiopathogenesis. We will discuss how mitochondrial dysfunction may impair ALP and in turn endorse Abeta production.
Mitochondrial dysfunction: a key indicator for AD pathology The mitochondrial cascade hypothesis postulated by Swerdlow and Khan (2004) states that, in the sporadic late-onset AD, mitochondrial dysfunction is the primary event that causes Abeta deposition, synaptic degeneration and NFT formation (Swerdlow and Khan, 2004). The key difference between the sporadic and familial AD is that in the last case, Abeta seems to be the primary pathological event, causing a secondary mitochondrial dysfunction (the Abeta cascade hypothesis). However, there is accumulating evidence from in vitro, in vivo and human studies suggesting that mitochondrial abnormalities may be indeed the initial event that trigger sporadic AD. In situ hybridization to mitochondrial DNA (mtDNA) and immunocytochemistry of cytochrome oxidase (COX) showed that mitochondrial abnormalities are intimately associated to AD (Castellani et al., 2002; Hirai et al., 2001). Indeed, it was shown that COX activity in post mortem AD brains was decrased (Kish et al., 1992; Cooper et al., 1993; Parker et al., 1994). Moreover, the cellular expression of COX subunit II and IV is reduced during aging and these age-related changes are more pronounced in AD (Ojaimi et al., 1999) suggesting that aging is a major risk factor for this disease. Furthermore, high levels of mtDNA mutations, linked to cytochrome oxidase deficiency, are observed more frequently in hippocampal pyramidal neurons of AD patients, compared to age-matched controls (Cottrell et al., 2002). Recently, it was described as a close association between an impaired respiratory chain function and Abeta deposition in dystrophic neuritis from AD patient's frontal cortex (Perez-Gracia et al., 2008).
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Moreover, several studies are being performed in AD patients' peripheral cells, based on the hypothesis that AD might be a systemic disease that affects several tissues in the body. It was demonstrated in fibroblasts from sporadic AD patients an abnormal mitochondrial distribution as compared to normal subjects fibroblasts (Wang et al., 2008). Data from our laboratory (Cardoso et al., 2004) showed that isolated mitochondria from AD platelets have a decrease in COX activity despite the fact that COX subunits are present at normal levels. Furthermore, it was observed that platelet ATP levels are decreased in AD while reactive oxygen species (ROS) are increased. So, we concluded that COX diminished catalytic activity is associated with ROS overproduction and energetic failure (Cardoso et al., 2004). Moreover, it was also shown that COX activity is significantly decreased in AD platelets (Bosetti et al., 2002). In order to overcome COX defect the hydrolytic activity of F0F1-ATPase increases significantly in sub-mitochondrial particles obtained from AD platelets as compared to the control subjects (Mancuso et al., 2003). To address the relevance and potential causes of COX defect in AD, the cytoplasmic hybrid (“cybrid”) technique, first described by King and Attardi (1989), has been applied (King and Attardi, 1989). The resulting AD cybrids showed a transferred COX defect and revealed a number of downstream consequences that recapitulate the pathology observed in AD brain (reviewed in Moreira et al., 2006). Results obtained with AD cybrids support the view that functionally relevant mtDNA mutation exists in AD subjects and accounts, at least partly, for the COX defect that is observed in multiple AD tissues. Alternatively, the Abeta cascade hypothesis proposes that Abeta is the primary cause of AD pathophysiology (Hardy and Selkoe, 2002). Strong support for this hypothesis came from studies in familial AD clusters that are caused by mutations of APP, presenilin1 and presenilin 2 genes. These mutations lead to an increase in Abeta levels and to a relatively early onset of dementia. With this evidence, many groups have developed transgenic mice in order to address AD etiopathology. Studies where mitochondria were isolated from a double Swedish and London mutant APP transgenic mice revealed a pronounced mitochondrial dysfunction with a decrease in mitochondrial membrane potential, a decrease in ATP levels, an inhibition of COX activity and an increase in ROS production (Hauptmann et al., 2009). These mitochondria abnormalities correlated with an increase in intracellular Abeta and were evident before Abeta extracellular deposition. A study by Aliev et al. (2003) positively correlates Abeta deposition with mitochondrial abnormalities in the vascular walls of an overexpressing APP transgenic mice (Aliev et al., 2003). Furthermore, a gene expression profile was carried out in an APP transgenic mouse model (Reddy et al., 2004) in order to establish which genes may be critical for cellular changes in AD progression. The authors observed that genes related to mitochondrial energy metabolism and apoptosis are up-regulated before and during the appearance of Abeta plaques. These results indicate that mitochondrial energy metabolism impairment, possibly by intraneuronal Abeta, could lead to an upregulation of mitochondrial genes as a compensatory response. In addition, Keil et al. (2004) demonstrated a decrease in mitochondrial membrane potential and a reduction in ATP levels in neurons of an APP transgenic mouse model when compared to littermate non transgenic mice (Keil et al., 2004). Mitochondria versus Abeta The modern era of molecular discovery in AD began in the mid1980s with the isolation and characterization of amyloid beta (Abeta) peptide as the principal constituent of senile plaques. Initially it was thought that Abeta was generated only under abnormal conditions, but in the early 1990s it was discovered that all cells normally secrete Abeta. Although it is still hypothesized the pathological role of Abeta peptides deposition (Abeta cascade hypothesis) in the brain, it is now believed that intracellular Abeta is the major pathological cause of AD,
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and yet no cure or even an efficient approach that could delay the devastating consequences of this disorder has been found (reviewed in Moreira et al., 2006; Pereira et al., 2005). Although previous studies provided clear evidence that mitochondria are involved in this process, the direct proof that links Abeta toxicity to mitochondria came only in the beginning of the 21st century, where the requirement of a functional mitochondria to Abeta induced cell death was established (Cardoso et al., 2001). Moreover, an Abeta interaction with mitochondrial proteins and with the inner mitochondrial membrane has been reported (Manczak et al., 2006). Recently it was demonstrated that Abeta is transported into mitochondria via the mitochondrial translocase of the outer membrane machinery (Hansson Petersen et al., 2008). Furthermore, data from our laboratory (Cardoso et al., 2001; Pereira et al., 1998, 1999) showed that Abeta peptides decrease the activity of mitochondrial respiratory chain complexes in PC12 and NT2 cells. Moreover, studies using transfected cell lines proved useful to correlate the increase in Abeta peptides production and a mitochondrial dysfunction. PC12 cells transfected with APP Swedish mutation show decreased COX activity and reduced ATP levels as compared to wild-type APP bearing cells and empty vector transfected cells (Keil et al., 2004). Furthermore, P19 cells stably transfected with human APP751 show abnormal mitochondria and decreased mitochondrial membrane potential (Grant et al., 1999). Anandatheerthavarada et al. (2003) demonstrated that the extent of APP mitochondrial targeting is correlated with mitochondrial dysfunction. Using HCN-1A cells transfected with APP Swedish mutation the authors clearly demonstrated a time-dependent accumulation of APP in the mitochondria with a decline in COX activity, reduced ATP synthesis and disruption of mitochondrial membrane potential (Anandatheerthavarada et al., 2003). Mitochondrial disturbances lead to a decrease in ATP levels that could induce Abeta misfolding. It has been reported that mitochondrial inhibitors-induced ATP depletion cause mitochondria transport alterations and induces changes in the intracellular distribution of tau (Escobar-Khondiker et al., 2007). Moreover, intraneuronal Abeta is intimately associated with neurodegeneration and death of neurons (reviewed in Pereira et al., 2005). Macroautophagy impairment in AD mediates Abeta production Macroautophagy is a continuous biological renewal mechanism that allows the degradation of the cell's own constituents by the lysosomes. This lysosomal pathway is the major route for degradation of intracellular organelles and long-lived proteins (Rideout et al., 2004). In macroautophagy (herein denominated autophagy) occurs the sequestration within a double-membrane-bounded vacuole, named autophagosome, of part of the cytosol. The degradation of cytosolic components occurs when the autophagosome fuses with the lysosome in the so called autophagolysosome (Klionsky et al., 2008). In the autophagolysome the degradation of the cargo and the recycling of amino acids and other monomeric molecules, occurs in order to generate ATP and building blocks essential to the cell metabolism (Cuervo, 2004; Yorimitsu and Klionsky, 2005). Autophagy is a tightly regulated process and in the brain there are normally basal low but steady levels of autophagy. This pathway is up-regulated under trophic stress or with the formation of misfolded protein aggregates that cannot be degraded in the ubiquitin proteasome pathway (UPS) (Eskelinen, 2008; Nixon, 2006). Consequently a link between autophagy and diseases associated with protein aggregation, like AD, has been recognized. Generally, misfolded proteins are problematic because they hinder normal cellular function when they accumulate to a high level. So a cellular adaptative response is activated, in which the cellular degradation systems are activated to eliminate abnormal protein aggregates. In AD, autophagy seems to have a dual role in Abeta accumulation. It seems to be initially
beneficial, but may also have a role in Abeta peptides formation and accumulation (Huang and Klionsky, 2007). Recently, it was shown that autophagosome–ysosome pathway (ALP) is compromised in AD (Nixon, 2007). Moreover, it was observed an abnormal accumulation of autophagic vacuoles (AV) in AD brains and in AD animal models (Nixon et al., 2005; Yu et al., 2005), which suggests a strong induction of autophagy. However, the autophagic key regulator protein beclin1 was reported to be decreased in affected brain regions of AD patients (Pickford et al., 2008). APP transgenic mice with a genetic reduction of beclin1 expression showed an increase in intraneuronal Abeta accumulation, extracellular Abeta deposition and profound neuronal abnormalities. The manipulation of beclin1 (increase) expression reduced both intracellular and extracellular Abeta pathology (Pickford et al., 2008) indicating a strong correlation between autophagy and APP metabolism. The neuritic dystrophy that is observed in AD brains is intimately correlated with a major increase of autophagic vacuoles (Nixon, 2007). Although, some evidences showed that even after a strong induction of autophagy, the AV clearance remains, in normal conditions, highly efficient. (Nixon et al. 2005) showed in AD that an impairment of AV maturation and clearance occurs. Moreover, an increased load in vesicular traffic will impair APP turn-over by ALP. The accumulation of AV and late-endosomes favour intracellular Abeta production that is now assumed to induce cellular cytotoxicity. Recently, it was demonstrated that Abeta peptides generation increases within the cell upon the accumulation of APP-rich AV (Nixon, 2006). The presence of APP, BACE and gamma-secretase in AVs from AD brains indicates that the formation of Abeta peptides might be regulated by autophagy (Yu et al., 2005). Based on the low levels of AVs detected in normal brain, it is conceivable that autophagy plays a minor role in constitutive Abeta buildup. Moreover, it is expected that a functional ALP degraded Abeta peptides within lysosomes (Nixon et al., 2008). However, in damaged neurites more APP-rich substrates are diverted to ALP with a delay in the AVlysosomal fusion. In AD the accumulation of AV without maturing in dystrophic neurites could contribute to amyloidogenesis with intracellular Abeta production (Yu et al., 2005). Nonetheless, it was recently observed that Abeta peptides added externally, not only decreased mitochondrial function (reviewed in Moreira et al., 2006) but also induced a strong autophagic response (Hung et al., 2009). Furthermore, the inhibition of autophagosome formation in Abeta treated cells, significantly enhanced its toxicity (Hung et al., 2009). Mitochondrial–lysosomal nexus in AD AVs accumulation in AD brain resembles the AV pattern generated in neurons as a result of lysosomal proteolysis inhibition and/or by autophagosome–lysosome fusion inhibition (Boland et al., 2008). Until now the reason for the robust accumulation of AVs in AD brains are still uncertain. Under normal conditions an equilibrium exists between autophagosome formation and clearance by lysosomes (Chu, 2006) named autophagic flux. Hence ALP disturbances in AD etiophatology may either result from an increase autophagy induction or by a compromised vesicular trafficking, hinder AV fusion with the lysosome (Kiselyov et al., 2007). Mitochondria failure deprives the cell of ATP and induces an increase in ROS production (reviewed in Moreira et al., 2006). Moreover, in postmitotic cells, a slow but continual accumulation of oxidative damage leads to an accumulation of non-functional mitochondria that have low membrane potential and often initiate a sequence of events resulting in autophagy induction. Therefore, mitochondrial-mediated protein oxidative damage and mitochondria defective accumulation could greatly induce autophagy. Under these cellular conditions mitochondrial ROS may also damage lysosomes, being lipofusin (age pigment, non-degradable polymeric compound) formation within the lysosomal compartment one of the most
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important consequences (Brunk et al., 1992). By the other end intact microtubules are needed for the efficient AV transport to the lysosomes. Evidence exists that microtubule depolymerizing agents disrupt vesicular transport and subsequently the fusion between AV and the lysosomes, inducing a rapid accumulation of autophagosomes (Kochl et al., 2006). Moreover, recent studies showed that a microtubule polymerizing agent prevented cognitive disturbances in AD mice model (Matsuoka et al., 2008). Interestingly, MPP+ and rotenone, two mitochondrial complex I inhibitors were shown to affect microtubule dynamics (Cappelletti et al., 2005; Ren and Feng, 2007). We proved that mitochondrial dependent ATP depletion and ROS generation induced an increase in depolymerized tubulin (Esteves et al., 2009) and (Esteves et al., unpublished work). Moreover MPP+ was shown to decrease anterograde and increase retrograde transport of both mitochondria and vesicles, probably due to a reduction of ATP supply to molecular motors (Cappelletti et al., 2005). Our preliminary results in AD cybrids, with dysfunctional mitochondria, showed an increase in AV. Moreover, cells without mitochondrial DNA (rho0 cells) that do not have a functional mitochondrial respiratory chain resemble AD brain cells with huge AVs accumulation (Cardoso, SM, unpublished data). So we hypothesize that the accumulation of dysfunctional mitochondria will impair microtubule network and activate autophagy creating a positive feedback loop that favors autophagosome formation without degradation by the lysosome, which contributes for Abeta peptides generation (Cataldo et al., 1996; Yu et al., 2005). Concluding remarks Age related neurodegenerative disorders will became a burden to the so called “western” societies. With the increased life expectancy due to valuable medical care/research we will assist to an already seen increase in age-related AD. Mitochondrial damage accumulates during the physiological process of aging, with greater consequences in postmitotic cells, such as neurons which are rarely or not at all replaced during life. Moreover, mitochondria are exceptionally primed to play a key role in neuronal cell survival. Apart from providing the cell with ATP, mitochondria are also central in the regulation of cell death since they harbor several death factors that are released upon apoptotic stimuli. Alterations in mitochondrial function, increased oxidative stress, and neurons dying by apoptosis have been detected in AD patients (reviewed in Pereira et al., 2005). These findings support the idea that mitochondria may trigger the abnormal onset of neuronal degeneration and death in AD. Results obtained from different models (from human brains, to cells) that mimic either AD familial forms (by introducing the altered genes) or sporadic forms (using sporadic AD cybrids) showed that mitochondria are involved, either directly or indirectly, in the cellular mechanisms that are believed to cause neuronal death. Recent evidence has shown that the Abeta peptide is generated from APP during autophagic turnover of APP-rich organelles supplied by both autophagy and endocytosis. Abeta generated during normal autophagy is subsequently degraded by lysosomes. Within neurons, autophagosomes and endosomes actively formed in synapses and along neuritic processes but efficient clearance of these compartments require their retrograde transport towards the neuronal cell body, where lysosomes are most concentrated. In AD, the maturation of autophagolysosomes and their retrograde transport are impeded, which leads to a massive accumulation of AV within large swellings along dystrophic and degenerating neurites. The combination of increased autophagy induction and defective clearance of Abeta-generating AV creates conditions favourable for intracellular Abeta accumulation in AD (Nixon, 2006). Moreover, synaptic loss in AD brain has been correlated with the soluble pool of Abeta rather than the fibrillar one (Klein et al., 2001). Since metabolic alterations, namely mitochondrial-induced metabolism dysfunction promotes cellular, organ and organism aging.
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Indeed, aging predisposes to a variety of diseases. Thus, we can make major inroads in many age-related diseases and disorders by amelioration of aging. Longevity and the associated mechanisms of ageing depend of multiple processes like metabolic control. Studies in several model systems showed the relevance of dysfunctional mitochondria signal to mammalian ageing. Consequently, metabolic adjustments or manipulation of nutritional status can extend life span and also postpone AD onset. References Aliev, G., Seyidova, D., Lamb, B.T., Obrenovich, M.E., Siedlak, S.L., Vinters, H.V., Friedland, R.P., LaManna, J.C., Smith, M.A., Perry, G., 2003. Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer diseaselike pathology in transgenic mice. Neurol. Res. 25, 665–674. Anandatheerthavarada, H.K., Biswas, G., Robin, M.A., Avadhani, N.G., 2003. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J. Cell Biol. 161, 41–54. Boland, B., Kumar, A., Lee, S., Platt, F.M., Wegiel, J., Yu, W.H., Nixon, R.A., 2008. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J. Neurosci. 28, 6926–6937. Bosetti, F., Brizzi, F., Barogi, S., Mancuso, M., Siciliano, G., Tendi, E.A., Murri, L., Rapoport, S.I., Solaini, G., 2002. Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease. Neurobiol. Aging 23, 371–376. Brunk, U.T., Jones, C.B., Sohal, R.S., 1992. A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis. Mutat. Res. 275, 395–403. Buchner, M., Huber, R., Sturchler-Pierrat, C., Staufenbiel, M., Riepe, M.W., 2002. Impaired hypoxic tolerance and altered protein binding of NADH in presymptomatic APP23 transgenic mice. Neuroscience 114, 285–289. Cappelletti, G., Surrey, T., Maci, R., 2005. The parkinsonism producing neurotoxin MPP+ affects microtubule dynamics by acting as a destabilising factor. FEBS Lett. 579, 4781–4786. Cardoso, S.M., Oliveira, C.R., 2003. Glutathione cycle impairment mediates A betainduced cell toxicity. Free Radic. Res. 37, 241–250. Cardoso, S.M., Santana, I., Swerdlow, R.H., Oliveira, C.R., 2004. Mitochondria dysfunction of Alzheimer's disease cybrids enhances Abeta toxicity. J. Neurochem. 89, 1417–1426. Cardoso, S.M., Santos, S., Swerdlow, R.H., Oliveira, C.R., 2001. Functional mitochondria are required for amyloid beta-mediated neurotoxicity. FASEB J. 15, 1439–1441. Castellani, R., Hirai, K., Aliev, G., Drew, K.L., Nunomura, A., Takeda, A., Cash, A.D., Obrenovich, M.E., Perry, G., Smith, M.A., 2002. Role of mitochondrial dysfunction in Alzheimer's disease. J. Neurosci. Res. 70, 357–360. Cataldo, A.M., Hamilton, D.J., Barnett, J.L., Paskevich, P.A., Nixon, R.A., 1996. Abnormalities of the endosomal–lysosomal system in Alzheimer's disease: relationship to disease pathogenesis. Adv. Exp. Med. Biol. 389, 271–280. Chu, C.T., 2006. Autophagic stress in neuronal injury and disease. J. Neuropathol. Exp. Neurol. 65, 423–432. Cooper, J.M., Wischik, C., Schapira, A.H., 1993. Mitochondrial function in Alzheimer's disease. Lancet 341, 969–970. Cottrell, D.A., Borthwick, G.M., Johnson, M.A., Ince, P.G., Turnbull, D.M., 2002. The role of cytochrome c oxidase deficient hippocampal neurones in Alzheimer's disease. Neuropathol. Appl. Neurobiol. 28, 390–396. Cuervo, A.M., 2004. Autophagy: many paths to the same end. Mol. Cell. Biochem. 263, 55–72. Dodart, J.C., Mathis, C., Bales, K.R., Paul, S.M., Ungerer, A., 1999. Early regional cerebral glucose hypometabolism in transgenic mice overexpressing the V717F betaamyloid precursor protein. Neurosci. Lett. 277, 49–52. Escobar-Khondiker, M., Hollerhage, M., Muriel, M.P., Champy, P., Bach, A., Depienne, C., Respondek, G., Yamada, E.S., Lannuzel, A., Yagi, T., Hirsch, E.C., Oertel, W.H., Jacob, R., Michel, P.P., Ruberg, M., Hoglinger, G.U., 2007. Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. J. Neurosci. 27, 7827–7837. Eskelinen, E.L., 2008. New insights into the mechanisms of macroautophagy in mammalian cells. Int. Rev. Cell Mol. Biol. 266, 207–247. Esteves, A.R., Arduino, D.M., Swerdlow, R.H., Oliveira, C.R., Cardoso, S.M., 2009. Oxidative Stress involvement in alpha-synuclein oligomerization in Parkinsons disease cybrids. Antioxid. Redox Signal. 11, 439–448. Gabuzda, D., Busciglio, J., Chen, L.B., Matsudaira, P., Yankner, B.A., 1994. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J. Biol. Chem. 269, 13623–13628. Grant, S.M., Shankar, S.L., Chalmers-Redman, R.M., Tatton, W.G., Szyf, M., Cuello, A.C., 1999. Mitochondrial abnormalities in neuroectodermal cells stably expressing human amyloid precursor protein (hAPP751). NeuroReport 10, 41–46. Hansson Petersen, C.A., Alikhani, N., Behbahani, H., Wiehager, B., Pavlov, P.F., Alafuzoff, I., Leinonen, V., Ito, A., Winblad, B., Glaser, E., Ankarcrona, M., 2008. The amyloid betapeptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc. Natl. Acad. Sci. U. S. A. 105, 13145–13150. Hardy, J., Selkoe, D.J., 2002. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356. Hauptmann, S., Scherping, I., Dröse, S., Brandt, U., Schulz, K.L., Jendrach, M., Leuner, K., Eckert, A., Müller, W.E., 2009. Mitochondrial dysfunction: an early event in
298
S.M. Cardoso et al. / Experimental Neurology 223 (2010) 294–298
Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol. Aging. 30, 1574–1586. Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R.L., Atwood, C.S., Johnson, A.B., Kress, Y., Vinters, H.V., Tabaton, M., Shimohama, S., Cash, A.D., Siedlak, S.L., Harris, P.L., Jones, P.K., Petersen, R.B., Perry, G., Smith, M.A., 2001. Mitochondrial abnormalities in Alzheimer's disease. J. Neurosci. 21, 3017–3023. Huang, J., Klionsky, D.J., 2007. Autophagy and human disease. Cell Cycle 6, 1837–1849. Hung, S.Y., Huang, W.P., Liou, H.C., Fu, W.M., 2009. Autophagy protects neuron from Abeta-induced cytotoxicity. Autophagy 5. Keil, U., Bonert, A., Marques, C.A., Scherping, I., Weyermann, J., Strosznajder, J.B., MullerSpahn, F., Haass, C., Czech, C., Pradier, L., Muller, W.E., Eckert, A., 2004. Amyloid betainduced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J. Biol. Chem. 279, 50310–50320. King, M.P., Attardi, G., 1989. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500–503. Kiselyov, K., Jennigs Jr., J.J., Rbaibi, Y., Chu, C.T., 2007. Autophagy, mitochondria and cell death in lysosomal storage diseases. Autophagy 3, 259–262. Kish, S.J., Bergeron, C., Rajput, A., Dozic, S., Mastrogiacomo, F., Chang, L.J., Wilson, J.M., DiStefano, L.M., Nobrega, J.N., 1992. Brain cytochrome oxidase in Alzheimer's disease. J. Neurochem. 59, 776–779. Klein, W.L., Krafft, G.A., Finch, C.E., 2001. Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 24, 219–224. Klein, W.L., Stine Jr., W.B., Teplow, D.B., 2004. Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer's disease. Neurobiol. Aging 25, 569–580. Klionsky, D.J., Elazar, Z., Seglen, P.O., Rubinsztein, D.C., 2008. Does bafilomycin A1 block the fusion of autophagosomes with lysosomes? Autophagy 4, 849–950. Kochl, R., Hu, X.W., Chan, E.Y., Tooze, S.A., 2006. Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes. Traffic 7, 129–145. Larsen, K.E., Sulzer, D., 2002. Autophagy in neurons: a review. Histol. Histopathol. 17, 897–908. Mancuso, M., Filosto, M., Bosetti, F., Ceravolo, R., Rocchi, A., Tognoni, G., Manca, M.L., Solaini, G., Siciliano, G., Murri, L., 2003. Decreased platelet cytochrome c oxidase activity is accompanied by increased blood lactate concentration during exercise in patients with Alzheimer disease. Exp. Neurol. 182, 421–426. Manczak, M., Anekonda, T.S., Henson, E., Park, B.S., Quinn, J., Reddy, P.H., 2006. 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. Hum. Mol. Genet. 15, 1437–1449. Matsuoka, Y., Jouroukhin, Y., Gray, A.J., Ma, L., Hirata-Fukae, C., Li, H.F., Feng, L., Lecanu, L., Walker, B.R., Planel, E., Arancio, O., Gozes, I., Aisen, P.S., 2008. A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer's disease. J. Pharmacol. Exp. Ther. 325, 146–153. Mattson, M.P., 2003. Will caloric restriction and folate protect against AD and PD? Neurology 60, 690–695. Moreira, P.I., Cardoso, S.M., Santos, M.S., Oliveira, C.R., 2006. The key role of mitochondria in Alzheimer's disease. J. Alzheimers Dis. 9, 101–110. Nixon, R.A., 2006. Autophagy in neurodegenerative disease: friend, foe or turncoat? Trends Neurosci. 29, 528–535.
Nixon, R.A., 2007. Autophagy, amyloidogenesis and Alzheimer disease. J. Cell Sci. 120, 4081–4091. Nixon, R.A., Wegiel, J., Kumar, A., Yu, W.H., Peterhoff, C., Cataldo, A., Cuervo, A.M., 2005. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 64, 113–122. Nixon, R.A., Yang, D.S., Lee, J.H., 2008. Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4, 590–599. Ojaimi, J., Masters, C.L., McLean, C., Opeskin, K., McKelvie, P., Byrne, E., 1999. Irregular distribution of cytochrome c oxidase protein subunits in aging and Alzheimer's disease. Ann. Neurol. 46, 656–660. Parker Jr, W.D., Parks, J., Filley, C.M., Kleinschmidt-DeMasters, B.K., 1994. Electron transport chain defects in Alzheimer's disease brain. Neurology 44, 1090–1096. Pereira, C., Agostinho, P., Moreira, P.I., Cardoso, S.M., Oliveira, C.R., 2005. Alzheimer's disease-associated neurotoxic mechanisms and neuroprotective strategies. Curr. Drug Targets CNS Neurol. Disord. 4, 383–403. Pereira, C., Santos, M.S., Oliveira, C., 1998. Mitochondrial function impairment induced by amyloid beta-peptide on PC12 cells. NeuroReport 9, 1749–1755. Pereira, C., Santos, M.S., Oliveira, C., 1999. Involvement of oxidative stress on the impairment of energy metabolism induced by A beta peptides on PC12 cells: protection by antioxidants. Neurobiol. Dis. 6, 209–219. Perez-Gracia, E., Torrejon-Escribano, B., Ferrer, I., 2008. Dystrophic neurites of senile plaques in Alzheimer's disease are deficient in cytochrome c oxidase. Acta Neuropathol. 116, 261–268. Pickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P.A., Small, S., Spencer, B., Rockenstein, E., Levine, B., Wyss-Coray, T., 2008. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Invest. 118, 2190–2199. Reddy, P.H., McWeeney, S., Park, B.S., Manczak, M., Gutala, R.V., Partovi, D., Jung, Y., Yau, V., Searles, R., Mori, M., Quinn, J., 2004. 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. Hum. Mol. Genet. 13, 1225–1240. Ren, Y., Feng, J., 2007. Rotenone selectively kills serotonergic neurons through a microtubule-dependent mechanism. J. Neurochem. 103, 303–311. Rideout, H.J., Lang-Rollin, I., Stefanis, L., 2004. Involvement of macroautophagy in the dissolution of neuronal inclusions. Int. J. Biochem. Cell Biol. 36, 2551–2562. Selkoe, D.J., 1993. Physiological production of the beta-amyloid protein and the mechanism of Alzheimer's disease. Trends Neurosci. 16, 403–409. Swerdlow, R.H., Khan, S.M., 2004. A “mitochondrial cascade hypothesis” for sporadic Alzheimer's disease. Med. Hypotheses 63, 8–20. Wang, X., Su, B., Fujioka, H., Zhu, X., 2008. Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer's disease patients. Am. J. Pathol. 173, 470–482. Yorimitsu, T., Klionsky, D.J., 2005. Atg11 links cargo to the vesicle-forming machinery in the cytoplasm to vacuole targeting pathway. Mol. Biol. Cell 16, 1593–1605. Yu, W.H., Cuervo, A.M., Kumar, A., Peterhoff, C.M., Schmidt, S.D., Lee, J.H., Mohan, P.S., Mercken, M., Farmery, M.R., Tjernberg, L.O., Jiang, Y., Duff, K., Uchiyama, Y., Naslund, J., Mathews, P.M., Cataldo, A.M., Nixon, R.A., 2005. Macroautophagy—a novel betaamyloid peptide-generating pathway activated in Alzheimer's disease. J. Cell Biol. 171, 87–98.
