J Neural Transm DOI 10.1007/s00702-015-1367-7
NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE
Cerebrovascular and mitochondrial abnormalities in Alzheimer’s disease: a brief overview Cristina Carvalho • So´nia C. Correia George Perry • Rudy J. Castellani • Paula I. Moreira
•
Received: 26 November 2014 / Accepted: 11 January 2015 Ó Springer-Verlag Wien 2015
Abstract Multiple lines of evidence suggest that vascular alterations contribute to Alzheimer’s disease (AD) pathogenesis. It is also well established that mitochondrial abnormalities occur early in course of AD. Here, we give an overview of the vascular and mitochondrial abnormalities occurring in AD, including mitochondrial alterations in vascular endothelial cells within the brain, which is emerging as a common feature that bridges cerebral vasculature and mitochondrial metabolism. Keywords Alzheimer’s disease Brain vasculature Mitochondria Oxidative stress
C. Carvalho S. C. Correia P. I. Moreira (&) CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal e-mail: [email protected]; [email protected] S. C. Correia Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal G. Perry (&) College of Sciences, The University of Texas at San Antonio, San Antonio, TX 78249, USA e-mail: [email protected] G. Perry Department of Pathology, Case Western Reserve University, Cleveland, OH, USA R. J. Castellani Division of Neuropathology, University of Maryland, Baltimore, MD, USA P. I. Moreira Faculty of Medicine, Institute of Physiology, University of Coimbra, 3000-354 Coimbra, Portugal
Cerebrovascular abnormalities in Alzheimer’s disease Alzheimer’s disease (AD) is the most common form of dementia among people aged 65 or older, affecting more than 35 million people worldwide. Clinically, AD is characterized by a progressive cognitive deterioration, together with impairments in behavior, language and visuospatial skills (Querfurth and LaFerla 2010). Neuropathologically, AD is characterized by selective neuronal and synaptic loss, deposition of extracellular senile plaques (SPs) mainly composed of amyloid b (Ab) peptide, and the presence of intracellular neurofibrillary degeneration (neurofibrillary tangles [NFTs]), dystrophic neurites, neuropil threads), comprised of hyperphosphorylated tau protein (Moreira 2012). The aggregates of Ab may occur in brain parenchyma, and in the walls of cerebral arteries leading to cerebral amyloid angiopathy (CAA) (Castellani et al. 2004). It was recently shown that capillary involvement by CAA in AD brains is associated with neuroinflammation, altered expression of tight junctions in endothelial cells and loss of blood–brain barrier (BBB) integrity (Carrano et al. 2012). Several other cerebrovascular abnormalities have been described in AD brains, including decreased microvascular density, basement membrane thickening, changes in vessels diameter, and impairment of glucose transport across the BBB (Humpel 2011). Alterations in brain vasculature also interfere with Ab clearance, promoting its deposition in brain tissue and within blood vessels = walls (Murray et al. 2011). In the brain, protein waste removal is partly performed by paravascular pathways, known as glymphatic system, which facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid. Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by
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cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. Recent studies showed that Ab and tau protein are partially removed from the brain parenchyma through the glymphatic system involving astroglia aquaporin 4 (Iliff et al. 2012, 2014). It was also reported that advancing age was associated with a dramatic decline in the efficiency of glymphatic system (Kress et al. 2014) suggesting that the impairment of glymphatic clearance contributes to cognitive decline and dementia among the elderly. Despite the structural changes in the vascular wall related to Ab deposition that predispose the patient to repeated episodes of blood vessel leakage or frank hemorrhage, recent anti-Ab monoclonal antibody therapies revealed unexpected side effects such as edema and hemorrhage. The efficacy of the humanized anti-Ab monoclonal antibody Bapineuzumab was tested in two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate AD; one involving 1,121 carriers of the apolipoprotein E (APOE) e4 allele and the other involving 1,331 noncarriers (Salloway et al. 2014). Bapineuzumab failed to arrest cognitive decline in AD patients, despite treatment differences in biomarkers observed in APOE e4 carriers. Differences were observed with respect to positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) and CSF phospho-tau concentrations in APOE e4 allele carriers but not in noncarriers. However, the major safety finding was Ab-related imaging abnormalities with edema among patients receiving bapineuzumab, this effect being dependent on bapineuzumab dose and APOE e4 allele number (Salloway et al. 2014). Phase 3 trials of the humanized monoclonal antibody solanezumab, which preferentially binds soluble Ab, involving mild-to-moderate AD revealed that the incidence of Ab-related imaging abnormalities with edema or hemorrhage was 0.9 % with solanezumab and 0.4 % with placebo for edema (P = 0.27) and 4.9 and 5.6 %, respectively, for hemorrhage (P = 0.49) (Doody et al. 2014). Two other monoclonal antibodies, gantenerumab, which preferentially bind to fibrillar Ab and crenezumab that preferentially binds to soluble, oligomeric and fibrillar Ab, are being tested in secondary prevention trials in presymptomatic subjects with familial AD. Solanezumab is also being tested in a prevention study in asymptomatic older subjects, who have positive PET scans for Ab deposits (Panza et al. 2014). These ongoing trials will reveal if Ab is a causative agent in AD. Magnetic resonance imaging (MRI), transcranial Doppler measurements, and single photon excitation computed tomography (SPECT) have established that the resting cerebral blood flow (CBF) is significantly reduced in AD patients (Carvalho et al. 2009). Arterial spin-labeling MRI found cerebral hypoperfusion in AD patients (Johnson
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et al. 2005). Functional MRI (fMRI) studies using blood oxygenation level dependent (BOLD) technique to measure increases in CBF during tasks that assess episodic memory demonstrated a delay in CBF response in patients with mild cognitive impairment, and was more pronounced in AD patients (Rombouts et al. 2005). Taken together, these data suggest that CBF reductions are present in the early stages of AD pathogenesis. A recent meta-analysis of transcranial Doppler studies (Sabayan et al. 2012) also revealed that patients with AD and vascular dementia have altered cerebrovascular hemodynamics, although those disturbances are more pronounced in patients with vascular dementia. A reduction in CBF leads to a decrease in oxygen and glucose delivery to the brain tissue (Roy and Rauk 2005) that can alter synaptic plasticity and promote mitochondrial dysfunction, oxidative stress, apoptosis (Carvalho et al. 2009, 2010) increase b-secretase activity, and production of Ab (Sun et al. 2006), a phenomenon that seems to be mediated by mitochondrial reactive oxygen species (ROS) (Guglielmotto et al. 2009). Overall, these findings indicate that vascular abnormalities in AD are intimately associated with impaired glucose/energy metabolism, and potentiate disease progression.
Mitochondrial abnormalities in Alzheimer’s disease Mitochondria play a pivotal role in cell survival or death as they regulate several key cellular processes including energy metabolism, reduction–oxidation potential, and apoptotic pathways. Maintaining mitochondrial homeostasis and bioenergetics in neurons in particular is even more critical, due to their almost complete dependence on mitochondrial-derived ATP (Moreira et al. 2007a, b). However, the production of energy is accompanied by the generation of ROS as by-products of the oxidative phosphorylation system. ROS are mainly produced at the respiratory chain complexes I and III, where electrons derived from reduced nicotinamide adenine dinucleotide (NADH) and succinate can directly react with oxygen or other electron acceptors and generate free radicals (Kushnareva et al. 2002; Chen et al. 2003). Although mitochondria contain an elaborate antioxidant defense system, the balance between ROS generation and antioxidant defense is disrupted in AD, resulting in cumulative oxidative damage of all categories of biological macromolecules (Moreira et al. 2007a, b). Accumulating evidence indicates that mitochondrial abnormalities and oxidative damage are early events in AD (Nunomura et al. 2001; Hirai et al. 2001). In female triple transgenic mice of AD, oxidative stress (Resende et al. 2008) and mitochondrial bioenergetic deficits (Yao et al. 2009) preceded AD pathology. Chou et al. (2011) also
Cerebrovascular and mitochondrial abnormalities
observed alterations in the mitochondrial proteome of the cerebral cortices of triple transgenic AD mice before the development of significant SPs and NFTs. More recently, Leuner et al. (2012) demonstrated that mitochondrial ROS are sufficient to trigger Ab production in vivo and in vitro. Evidence from postmortem AD brain and fibroblasts showed an impaired activity of three tricarboxylic acid cycle enzymatic complexes, pyruvate dehydrogenase, isocitrate dehydrogenase and a-ketoglutarate dehydrogenase (Bubber et al. 2005; Huang et al. 2003). A reduction in the activity of mitochondrial complexes I, III and IV was also found in platelets and lymphocytes from AD patients and postmortem brain tissue Kish et al. 1992; Parker et al. 1994; Bosetti et al. 2002; Valla et al. 2006). Several in vitro studies corroborate the idea that mitochondria are central to AD pathogenesis. It was previously shown that Ab1–40 induced a significant increase in hydrogen peroxide (H2O2) production in brain mitochondria isolated from diabetic rats (Moreira et al. 2005a, b). Ab was shown to potentiate the opening of the mitochondrial permeability transition pore (PTP) induced by Ca2? (Moreira et al. 2001, 2002), which contributes to the release of proapoptotic proteins such as cytochrome c and apoptosis-inducing factor. The interaction of cyclophilin D, an integral part of the PTP, with mitochondrial Ab potentiates mitochondrial, neuronal and synaptic stress (Du et al. 2008). Cyclophilin D deficiency substantially improved learning and memory and synaptic function in an AD mouse model and alleviated Ab-mediated reduction of long-term potentiation (Du et al. 2008). It was also reported that sporadic AD fibroblasts presented alterations in mitochondria morphology and distribution, which are due to a decrease in dynamin-like protein 1 (DLP1), a regulator of mitochondrial fission and distribution (Wang et al. 2008a). The overproduction of Ab caused abnormal mitochondrial dynamics, affecting differences in morphology, distribution, and function via differential modulation of mitochondrial fission/fusion proteins (Wang et al. 2008b). Similarly, Cho et al. (2009) found that nitric oxide produced in response to Ab triggers mitochondrial fission, synaptic loss, and neuronal damage, in part via S-nitrosylation of DLP1. An increased autophagic degradation of mitochondria in AD brain has also been shown (Moreira et al. 2007a, b). More recently, it was demonstrated that parkin-mediated clearance of ubiquitinated Ab may act in parallel with autophagy to clear molecular debris and defective mitochondria and restore neurotransmitter balance (Khandelwal et al. 2011). Cerebral endothelial mitochondria: what is their role in Alzheimer’s disease? Cerebral blood vessels are highly metabolically active, with a greater complement of mitochondria in
cerebrovascular endothelium compared to other vascular beds (Nag 2002). This reflects the unique role of cerebral endothelial cells in maintaining autoregulation of cerebral blood flow as well as the precise matching of local blood flow to brain metabolic activity. Highly metabolically active cells are particularly subject to progressive mitochondrial abnormalities due to oxidative stress, in part due to mitochondrial ROS. Many injuries or insults thought to initiate BBB dysfunction are directly linked to mitochondrial abnormalities and oxidative stress and damage (Kolev et al. 2003; Pu et al. 2009). Studies of the BBB in AD patients have shown decreased mitochondrial content (Claudio 1996). It was previously shown that Ab-induced cerebral endothelial cell death is associated with mitochondrial dysfunction and caspase activation (Xu et al. 2001). Ab affected the integrity of nuclear and mitochondrial DNA, activated caspase 8 and caspase 3, and caused apoptosis in brain endothelial cells, which could be prevented by zVAD-fmk, a broad-spectrum caspase inhibitor, or by the antioxidant N-acetylcysteine (Xu et al. 2001). Furthermore, the exposure of brain endothelial cells to oxidized lipids increased nitric oxide and ROS production and stimulated translocation of the proapoptotic protein Bax (Hamdheydari et al. 2003; Chang et al. 2011). However, the activation of the death pathway involving Bax, cytochrome c and caspase in cerebral endothelial cells was attenuated by the antioxidant resveratrol (Chang et al. 2011). These findings suggest that cerebral endothelial mitochondria and oxidative stress are also implicated in AD pathology.
Conclusions Accumulating evidence indicates that vascular abnormalities are early events in AD pathogenesis. This idea is supported by several studies showing that vascular risk factors such as diabetes, stroke, cardiovascular disease and hypercholesterolemia increase the risk of AD (Moreira 2012; Carrano et al. 2012). Other important factors in disease pathogenesis are mitochondria since several studies demonstrate that mitochondrial abnormalities are causative agents in AD. However, the role of brain endothelial mitochondria in the AD is only beginning to be unraveled. Thus, more studies are needed to clarify the role of these organelles in this cell type, in AD pathogenesis. Acknowledgements The authors’ work is supported by Quadro de Refereˆncia Estrate´gico Nacional (QREN DO-IT) and Alzheimer’s Association (NIRG-13-282387), by the Semmes Foundation, and by a grant from the National Institute on Minority Health and Health Disparities (G12MD007591) from the National Institutes of Health.
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References Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA et al (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 Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 57:695–703 Carrano A, Hoozemans JJ, van der Vies SM, van Horssen J, de Vries HE, Rozemuller AJ (2012) Neuroinflammation and blood-brain barrier changes in capillary amyloid angiopathy. Neurodegener Dis 10:329–331 Carvalho C, Correia SC, Santos RX, Cardoso S, Moreira PI, Clark TA et al (2009) Role of mitochondrial-mediated signaling pathways in Alzheimer disease and hypoxia. J Bioenerg Biomembr 41:433–440 Carvalho C, Santos MS, Baldeiras I, Oliveira CR, Seic¸a R, Moreira PI (2010) Chronic hypoxia potentiates age-related oxidative imbalance in brain vessels and synaptosomes. Curr Neurovasc Res 7:288–300 Castellani RJ, Smith MA, Perry G, Friedland RP (2004) Cerebral amyloid angiopathy: major contributor or decorative response to Alzheimer’s disease pathogenesis. Neurobiol Dis 25:599–602 Chang HC, Chen TG, Tai YT, Chen TL, Chiu WT, Chen RM (2011) Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells. J Cereb Blood Flow Metab 3:842–854 Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ (2003) Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem 278:36027–36031 Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z et al (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324:102–105 Chou JL, Shenoy DV, Thomas N, Choudhary PK, Laferla FM, Goodman SR et al (2011) Early dysregulation of the mitochondrial proteome in a mouse model of Alzheimer’s disease. J Proteomics 74:466–479 Claudio L (1996) Ultrastructural features of the blood–brain barrier in biopsy tissue from Alzheimer’s disease patients. Acta Neuropathol 91:6–14 Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S et al (2014) Alzheimer’s Disease Cooperative Study Steering Committee; Solanezumab Study Group. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370:311–321 Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM et al (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105 Guglielmotto M, Aragno M, Autelli R, Giliberto L, Novo E, Colombatto S et al (2009) The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha. J Neurochem 108:1045–1056 Hamdheydari L, Christov A, Ottman T, Hensley K, Grammas P (2003) Oxidized LDLs affect nitric oxide and radical generation in brain endothelial cells. Biochem Biophys Res Comm 311:486–490 Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS et al (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023 Huang HM, Ou HC, Xu H, Chen HL, Fowler C, Gibson GE (2003) Inhibition of alpha ketoglutarate dehydrogenase complex promotes cytochrome c release from mitochondria, caspase-3 activation, and necrotic cell death. J Neurosci Res 74:309–317
123
Humpel C (2011) Chronic mild cerebrovascular dysfunction as a cause for Alzheimer’s disease? Exp Gerontol 46:225–232 Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid b. Sci Transl Med 4:147 Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L et al (2014) Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34:16180–16193 Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ et al (2005) Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 234:851–859 Khandelwal PJ, Herman AM, Hoe HS, Rebeck GW, Moussa CE (2011) Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models. Hum Mol Genet 20:2091–2102 Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ et al (1992) Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem 59:776–779 Kolev K, Skopa´l J, Simon L, Csonka E, Machovich R, Nagy Z (2003) Matrix metalloproteinase-9 expression in post-hypoxic human brain capillary endothelial cells: H2O2 as a trigger and NFkappaB as a signal transducer. Thromb Haemost 90:528–537 Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D et al (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76:845–861 Kushnareva Y, Murphy AN, Andreyev A (2002) Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)? oxidation–reduction state. Biochem J 368:545–553 Leuner K, Schu¨tt T, Kurz C, Eckert SH, Schiller C, Occhipinti A et al (2012) Mitochondria-derived ROS lead to enhanced amyloid beta formation. Antioxid Redox Signal 16:1421–1433 Moreira PI (2012) Alzheimer’s disease and diabetes: an integrative view of the role of mitochondria, oxidative stress and insulin. J Alzheimers Dis 30:S199–S215 Moreira PI, Santos MS, Moreno A, Oliveira C (2001) Amyloid betapeptide promotes permeability transition pore in brain mitochondria. Biosci Rep 21:789–800 Moreira PI, Santos MS, Moreno A, Rego AC, Oliveira C (2002) Effect of amyloid beta-peptide on permeability transition pore: a comparative study. J Neurosci Res 69:257–267 Moreira PI, Santos MS, Sena C, Nunes E, Seic¸a R, Oliveira CR (2005a) CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats. Exp Neurol 196:112–119 Moreira PI, Santos MS, Sena C, Seic¸a R, Oliveira CR (2005b) Insulin protects against amyloid beta-peptide toxicity in brain mitochondria of diabetic rats. Neurobiol Dis 18:628–637 Moreira PI, Santos MS, Oliveira CR (2007a) Alzheimer’s disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal 9:1621–1630 Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M et al (2007b) Autophagocytosis of mitochondria is prominent in Alzheimer disease. J Neuropathol Exp Neurol 66:525–532 Murray IV, Proza JF, Sohrabji F, Lawler JM (2011) Vascular and metabolic dysfunction in Alzheimer’s disease: a review. Exp Biol Med (Maywood) 236:772–782 Nag S (2002) The blood-brain barrier and cerebral angiogenesis: lessons from the cold-injury model. Trends Mol Med 8:38–44 Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK et al (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767
Cerebrovascular and mitochondrial abnormalities Panza F et al (2014) Efficacy and safety studies of gantenerumab in patients with Alzheimer’s disease. Expert Rev Neurother 14:973–986 Parker WD Jr, Mahr NJ, Filley CM, Parks JK, Hughes D, Young DA et al (1994) et al. Reduced platelet cytochrome c oxidase activity in Alzheimer’s disease. Neurology 44:1086–1090 Pu PB, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res 43:348–364 Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344 Resende R, Moreira PI, Proenc¸a T, Deshpande A, Busciglio J, Pereira C et al (2008) Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic Biol Med 44:2051–2057 Rombouts SA, Goekoop R, Stam CJ, Barkhof F, Scheltens P (2005) Delayed rather than decreased BOLD response as a marker for early Alzheimer’s disease. Neuroimage 26:1078–1085 Roy S, Rauk A (2005) Alzheimer’s disease and the ‘ABSENT’ hypothesis: mechanism for amyloid beta endothelial and neuronal toxicity. Med Hypotheses 65:123–137 Sabayan B, Jansen S, Oleksik AM, van Osch MJ, van Buchem MA, van Vliet P et al (2012) Cerebrovascular hemodynamics in Alzheimer’s disease and vascular dementia: a meta-analysis of transcranial Doppler studies. Ageing Res Rev 11:271–277 Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M et al (2014) Bapineuzumab 301 and 302 Clinical Trial Investigators. Two phase 3 trials of bapineuzumab in mild-tomoderate Alzheimer’s disease. N Engl J Med 370:322–333
Sun X, He G, Qing H, Zhou W, Dobie F, Cai F et al (2006) Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA 103:18727–18732 Valla J, Schneider L, Niedzielko T, Coon KD, Caselli R, Sabbagh MN et al (2006) Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment. Mitochondrion 6:323–330 Wang X, Su B, Fujioka H, Zhu X (2008a) 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 Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y et al (2008b) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 105:19318–19323 Xu J, Chen S, Ku G, Ahmed SH, Xu J, Chen H et al (2001) Amyloid beta peptide-induced cerebral endothelial cell death involves mitochondrial dysfunction and caspase activation. J Cereb Blood Flow Metab 21:702–710 Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 106:14670–14675
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NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE
Cerebrovascular and mitochondrial abnormalities in Alzheimer’s disease: a brief overview Cristina Carvalho • So´nia C. Correia George Perry • Rudy J. Castellani • Paula I. Moreira
•
Received: 26 November 2014 / Accepted: 11 January 2015 Ó Springer-Verlag Wien 2015
Abstract Multiple lines of evidence suggest that vascular alterations contribute to Alzheimer’s disease (AD) pathogenesis. It is also well established that mitochondrial abnormalities occur early in course of AD. Here, we give an overview of the vascular and mitochondrial abnormalities occurring in AD, including mitochondrial alterations in vascular endothelial cells within the brain, which is emerging as a common feature that bridges cerebral vasculature and mitochondrial metabolism. Keywords Alzheimer’s disease Brain vasculature Mitochondria Oxidative stress
C. Carvalho S. C. Correia P. I. Moreira (&) CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal e-mail: [email protected]; [email protected] S. C. Correia Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal G. Perry (&) College of Sciences, The University of Texas at San Antonio, San Antonio, TX 78249, USA e-mail: [email protected] G. Perry Department of Pathology, Case Western Reserve University, Cleveland, OH, USA R. J. Castellani Division of Neuropathology, University of Maryland, Baltimore, MD, USA P. I. Moreira Faculty of Medicine, Institute of Physiology, University of Coimbra, 3000-354 Coimbra, Portugal
Cerebrovascular abnormalities in Alzheimer’s disease Alzheimer’s disease (AD) is the most common form of dementia among people aged 65 or older, affecting more than 35 million people worldwide. Clinically, AD is characterized by a progressive cognitive deterioration, together with impairments in behavior, language and visuospatial skills (Querfurth and LaFerla 2010). Neuropathologically, AD is characterized by selective neuronal and synaptic loss, deposition of extracellular senile plaques (SPs) mainly composed of amyloid b (Ab) peptide, and the presence of intracellular neurofibrillary degeneration (neurofibrillary tangles [NFTs]), dystrophic neurites, neuropil threads), comprised of hyperphosphorylated tau protein (Moreira 2012). The aggregates of Ab may occur in brain parenchyma, and in the walls of cerebral arteries leading to cerebral amyloid angiopathy (CAA) (Castellani et al. 2004). It was recently shown that capillary involvement by CAA in AD brains is associated with neuroinflammation, altered expression of tight junctions in endothelial cells and loss of blood–brain barrier (BBB) integrity (Carrano et al. 2012). Several other cerebrovascular abnormalities have been described in AD brains, including decreased microvascular density, basement membrane thickening, changes in vessels diameter, and impairment of glucose transport across the BBB (Humpel 2011). Alterations in brain vasculature also interfere with Ab clearance, promoting its deposition in brain tissue and within blood vessels = walls (Murray et al. 2011). In the brain, protein waste removal is partly performed by paravascular pathways, known as glymphatic system, which facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid. Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by
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cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. Recent studies showed that Ab and tau protein are partially removed from the brain parenchyma through the glymphatic system involving astroglia aquaporin 4 (Iliff et al. 2012, 2014). It was also reported that advancing age was associated with a dramatic decline in the efficiency of glymphatic system (Kress et al. 2014) suggesting that the impairment of glymphatic clearance contributes to cognitive decline and dementia among the elderly. Despite the structural changes in the vascular wall related to Ab deposition that predispose the patient to repeated episodes of blood vessel leakage or frank hemorrhage, recent anti-Ab monoclonal antibody therapies revealed unexpected side effects such as edema and hemorrhage. The efficacy of the humanized anti-Ab monoclonal antibody Bapineuzumab was tested in two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate AD; one involving 1,121 carriers of the apolipoprotein E (APOE) e4 allele and the other involving 1,331 noncarriers (Salloway et al. 2014). Bapineuzumab failed to arrest cognitive decline in AD patients, despite treatment differences in biomarkers observed in APOE e4 carriers. Differences were observed with respect to positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) and CSF phospho-tau concentrations in APOE e4 allele carriers but not in noncarriers. However, the major safety finding was Ab-related imaging abnormalities with edema among patients receiving bapineuzumab, this effect being dependent on bapineuzumab dose and APOE e4 allele number (Salloway et al. 2014). Phase 3 trials of the humanized monoclonal antibody solanezumab, which preferentially binds soluble Ab, involving mild-to-moderate AD revealed that the incidence of Ab-related imaging abnormalities with edema or hemorrhage was 0.9 % with solanezumab and 0.4 % with placebo for edema (P = 0.27) and 4.9 and 5.6 %, respectively, for hemorrhage (P = 0.49) (Doody et al. 2014). Two other monoclonal antibodies, gantenerumab, which preferentially bind to fibrillar Ab and crenezumab that preferentially binds to soluble, oligomeric and fibrillar Ab, are being tested in secondary prevention trials in presymptomatic subjects with familial AD. Solanezumab is also being tested in a prevention study in asymptomatic older subjects, who have positive PET scans for Ab deposits (Panza et al. 2014). These ongoing trials will reveal if Ab is a causative agent in AD. Magnetic resonance imaging (MRI), transcranial Doppler measurements, and single photon excitation computed tomography (SPECT) have established that the resting cerebral blood flow (CBF) is significantly reduced in AD patients (Carvalho et al. 2009). Arterial spin-labeling MRI found cerebral hypoperfusion in AD patients (Johnson
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et al. 2005). Functional MRI (fMRI) studies using blood oxygenation level dependent (BOLD) technique to measure increases in CBF during tasks that assess episodic memory demonstrated a delay in CBF response in patients with mild cognitive impairment, and was more pronounced in AD patients (Rombouts et al. 2005). Taken together, these data suggest that CBF reductions are present in the early stages of AD pathogenesis. A recent meta-analysis of transcranial Doppler studies (Sabayan et al. 2012) also revealed that patients with AD and vascular dementia have altered cerebrovascular hemodynamics, although those disturbances are more pronounced in patients with vascular dementia. A reduction in CBF leads to a decrease in oxygen and glucose delivery to the brain tissue (Roy and Rauk 2005) that can alter synaptic plasticity and promote mitochondrial dysfunction, oxidative stress, apoptosis (Carvalho et al. 2009, 2010) increase b-secretase activity, and production of Ab (Sun et al. 2006), a phenomenon that seems to be mediated by mitochondrial reactive oxygen species (ROS) (Guglielmotto et al. 2009). Overall, these findings indicate that vascular abnormalities in AD are intimately associated with impaired glucose/energy metabolism, and potentiate disease progression.
Mitochondrial abnormalities in Alzheimer’s disease Mitochondria play a pivotal role in cell survival or death as they regulate several key cellular processes including energy metabolism, reduction–oxidation potential, and apoptotic pathways. Maintaining mitochondrial homeostasis and bioenergetics in neurons in particular is even more critical, due to their almost complete dependence on mitochondrial-derived ATP (Moreira et al. 2007a, b). However, the production of energy is accompanied by the generation of ROS as by-products of the oxidative phosphorylation system. ROS are mainly produced at the respiratory chain complexes I and III, where electrons derived from reduced nicotinamide adenine dinucleotide (NADH) and succinate can directly react with oxygen or other electron acceptors and generate free radicals (Kushnareva et al. 2002; Chen et al. 2003). Although mitochondria contain an elaborate antioxidant defense system, the balance between ROS generation and antioxidant defense is disrupted in AD, resulting in cumulative oxidative damage of all categories of biological macromolecules (Moreira et al. 2007a, b). Accumulating evidence indicates that mitochondrial abnormalities and oxidative damage are early events in AD (Nunomura et al. 2001; Hirai et al. 2001). In female triple transgenic mice of AD, oxidative stress (Resende et al. 2008) and mitochondrial bioenergetic deficits (Yao et al. 2009) preceded AD pathology. Chou et al. (2011) also
Cerebrovascular and mitochondrial abnormalities
observed alterations in the mitochondrial proteome of the cerebral cortices of triple transgenic AD mice before the development of significant SPs and NFTs. More recently, Leuner et al. (2012) demonstrated that mitochondrial ROS are sufficient to trigger Ab production in vivo and in vitro. Evidence from postmortem AD brain and fibroblasts showed an impaired activity of three tricarboxylic acid cycle enzymatic complexes, pyruvate dehydrogenase, isocitrate dehydrogenase and a-ketoglutarate dehydrogenase (Bubber et al. 2005; Huang et al. 2003). A reduction in the activity of mitochondrial complexes I, III and IV was also found in platelets and lymphocytes from AD patients and postmortem brain tissue Kish et al. 1992; Parker et al. 1994; Bosetti et al. 2002; Valla et al. 2006). Several in vitro studies corroborate the idea that mitochondria are central to AD pathogenesis. It was previously shown that Ab1–40 induced a significant increase in hydrogen peroxide (H2O2) production in brain mitochondria isolated from diabetic rats (Moreira et al. 2005a, b). Ab was shown to potentiate the opening of the mitochondrial permeability transition pore (PTP) induced by Ca2? (Moreira et al. 2001, 2002), which contributes to the release of proapoptotic proteins such as cytochrome c and apoptosis-inducing factor. The interaction of cyclophilin D, an integral part of the PTP, with mitochondrial Ab potentiates mitochondrial, neuronal and synaptic stress (Du et al. 2008). Cyclophilin D deficiency substantially improved learning and memory and synaptic function in an AD mouse model and alleviated Ab-mediated reduction of long-term potentiation (Du et al. 2008). It was also reported that sporadic AD fibroblasts presented alterations in mitochondria morphology and distribution, which are due to a decrease in dynamin-like protein 1 (DLP1), a regulator of mitochondrial fission and distribution (Wang et al. 2008a). The overproduction of Ab caused abnormal mitochondrial dynamics, affecting differences in morphology, distribution, and function via differential modulation of mitochondrial fission/fusion proteins (Wang et al. 2008b). Similarly, Cho et al. (2009) found that nitric oxide produced in response to Ab triggers mitochondrial fission, synaptic loss, and neuronal damage, in part via S-nitrosylation of DLP1. An increased autophagic degradation of mitochondria in AD brain has also been shown (Moreira et al. 2007a, b). More recently, it was demonstrated that parkin-mediated clearance of ubiquitinated Ab may act in parallel with autophagy to clear molecular debris and defective mitochondria and restore neurotransmitter balance (Khandelwal et al. 2011). Cerebral endothelial mitochondria: what is their role in Alzheimer’s disease? Cerebral blood vessels are highly metabolically active, with a greater complement of mitochondria in
cerebrovascular endothelium compared to other vascular beds (Nag 2002). This reflects the unique role of cerebral endothelial cells in maintaining autoregulation of cerebral blood flow as well as the precise matching of local blood flow to brain metabolic activity. Highly metabolically active cells are particularly subject to progressive mitochondrial abnormalities due to oxidative stress, in part due to mitochondrial ROS. Many injuries or insults thought to initiate BBB dysfunction are directly linked to mitochondrial abnormalities and oxidative stress and damage (Kolev et al. 2003; Pu et al. 2009). Studies of the BBB in AD patients have shown decreased mitochondrial content (Claudio 1996). It was previously shown that Ab-induced cerebral endothelial cell death is associated with mitochondrial dysfunction and caspase activation (Xu et al. 2001). Ab affected the integrity of nuclear and mitochondrial DNA, activated caspase 8 and caspase 3, and caused apoptosis in brain endothelial cells, which could be prevented by zVAD-fmk, a broad-spectrum caspase inhibitor, or by the antioxidant N-acetylcysteine (Xu et al. 2001). Furthermore, the exposure of brain endothelial cells to oxidized lipids increased nitric oxide and ROS production and stimulated translocation of the proapoptotic protein Bax (Hamdheydari et al. 2003; Chang et al. 2011). However, the activation of the death pathway involving Bax, cytochrome c and caspase in cerebral endothelial cells was attenuated by the antioxidant resveratrol (Chang et al. 2011). These findings suggest that cerebral endothelial mitochondria and oxidative stress are also implicated in AD pathology.
Conclusions Accumulating evidence indicates that vascular abnormalities are early events in AD pathogenesis. This idea is supported by several studies showing that vascular risk factors such as diabetes, stroke, cardiovascular disease and hypercholesterolemia increase the risk of AD (Moreira 2012; Carrano et al. 2012). Other important factors in disease pathogenesis are mitochondria since several studies demonstrate that mitochondrial abnormalities are causative agents in AD. However, the role of brain endothelial mitochondria in the AD is only beginning to be unraveled. Thus, more studies are needed to clarify the role of these organelles in this cell type, in AD pathogenesis. Acknowledgements The authors’ work is supported by Quadro de Refereˆncia Estrate´gico Nacional (QREN DO-IT) and Alzheimer’s Association (NIRG-13-282387), by the Semmes Foundation, and by a grant from the National Institute on Minority Health and Health Disparities (G12MD007591) from the National Institutes of Health.
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References Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA et al (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 Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 57:695–703 Carrano A, Hoozemans JJ, van der Vies SM, van Horssen J, de Vries HE, Rozemuller AJ (2012) Neuroinflammation and blood-brain barrier changes in capillary amyloid angiopathy. Neurodegener Dis 10:329–331 Carvalho C, Correia SC, Santos RX, Cardoso S, Moreira PI, Clark TA et al (2009) Role of mitochondrial-mediated signaling pathways in Alzheimer disease and hypoxia. J Bioenerg Biomembr 41:433–440 Carvalho C, Santos MS, Baldeiras I, Oliveira CR, Seic¸a R, Moreira PI (2010) Chronic hypoxia potentiates age-related oxidative imbalance in brain vessels and synaptosomes. Curr Neurovasc Res 7:288–300 Castellani RJ, Smith MA, Perry G, Friedland RP (2004) Cerebral amyloid angiopathy: major contributor or decorative response to Alzheimer’s disease pathogenesis. Neurobiol Dis 25:599–602 Chang HC, Chen TG, Tai YT, Chen TL, Chiu WT, Chen RM (2011) Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells. J Cereb Blood Flow Metab 3:842–854 Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ (2003) Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem 278:36027–36031 Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z et al (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324:102–105 Chou JL, Shenoy DV, Thomas N, Choudhary PK, Laferla FM, Goodman SR et al (2011) Early dysregulation of the mitochondrial proteome in a mouse model of Alzheimer’s disease. J Proteomics 74:466–479 Claudio L (1996) Ultrastructural features of the blood–brain barrier in biopsy tissue from Alzheimer’s disease patients. Acta Neuropathol 91:6–14 Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S et al (2014) Alzheimer’s Disease Cooperative Study Steering Committee; Solanezumab Study Group. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370:311–321 Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM et al (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105 Guglielmotto M, Aragno M, Autelli R, Giliberto L, Novo E, Colombatto S et al (2009) The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha. J Neurochem 108:1045–1056 Hamdheydari L, Christov A, Ottman T, Hensley K, Grammas P (2003) Oxidized LDLs affect nitric oxide and radical generation in brain endothelial cells. Biochem Biophys Res Comm 311:486–490 Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS et al (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023 Huang HM, Ou HC, Xu H, Chen HL, Fowler C, Gibson GE (2003) Inhibition of alpha ketoglutarate dehydrogenase complex promotes cytochrome c release from mitochondria, caspase-3 activation, and necrotic cell death. J Neurosci Res 74:309–317
123
Humpel C (2011) Chronic mild cerebrovascular dysfunction as a cause for Alzheimer’s disease? Exp Gerontol 46:225–232 Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid b. Sci Transl Med 4:147 Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L et al (2014) Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34:16180–16193 Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ et al (2005) Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 234:851–859 Khandelwal PJ, Herman AM, Hoe HS, Rebeck GW, Moussa CE (2011) Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models. Hum Mol Genet 20:2091–2102 Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ et al (1992) Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem 59:776–779 Kolev K, Skopa´l J, Simon L, Csonka E, Machovich R, Nagy Z (2003) Matrix metalloproteinase-9 expression in post-hypoxic human brain capillary endothelial cells: H2O2 as a trigger and NFkappaB as a signal transducer. Thromb Haemost 90:528–537 Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D et al (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76:845–861 Kushnareva Y, Murphy AN, Andreyev A (2002) Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)? oxidation–reduction state. Biochem J 368:545–553 Leuner K, Schu¨tt T, Kurz C, Eckert SH, Schiller C, Occhipinti A et al (2012) Mitochondria-derived ROS lead to enhanced amyloid beta formation. Antioxid Redox Signal 16:1421–1433 Moreira PI (2012) Alzheimer’s disease and diabetes: an integrative view of the role of mitochondria, oxidative stress and insulin. J Alzheimers Dis 30:S199–S215 Moreira PI, Santos MS, Moreno A, Oliveira C (2001) Amyloid betapeptide promotes permeability transition pore in brain mitochondria. Biosci Rep 21:789–800 Moreira PI, Santos MS, Moreno A, Rego AC, Oliveira C (2002) Effect of amyloid beta-peptide on permeability transition pore: a comparative study. J Neurosci Res 69:257–267 Moreira PI, Santos MS, Sena C, Nunes E, Seic¸a R, Oliveira CR (2005a) CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats. Exp Neurol 196:112–119 Moreira PI, Santos MS, Sena C, Seic¸a R, Oliveira CR (2005b) Insulin protects against amyloid beta-peptide toxicity in brain mitochondria of diabetic rats. Neurobiol Dis 18:628–637 Moreira PI, Santos MS, Oliveira CR (2007a) Alzheimer’s disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal 9:1621–1630 Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M et al (2007b) Autophagocytosis of mitochondria is prominent in Alzheimer disease. J Neuropathol Exp Neurol 66:525–532 Murray IV, Proza JF, Sohrabji F, Lawler JM (2011) Vascular and metabolic dysfunction in Alzheimer’s disease: a review. Exp Biol Med (Maywood) 236:772–782 Nag S (2002) The blood-brain barrier and cerebral angiogenesis: lessons from the cold-injury model. Trends Mol Med 8:38–44 Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK et al (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767
Cerebrovascular and mitochondrial abnormalities Panza F et al (2014) Efficacy and safety studies of gantenerumab in patients with Alzheimer’s disease. Expert Rev Neurother 14:973–986 Parker WD Jr, Mahr NJ, Filley CM, Parks JK, Hughes D, Young DA et al (1994) et al. Reduced platelet cytochrome c oxidase activity in Alzheimer’s disease. Neurology 44:1086–1090 Pu PB, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res 43:348–364 Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344 Resende R, Moreira PI, Proenc¸a T, Deshpande A, Busciglio J, Pereira C et al (2008) Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic Biol Med 44:2051–2057 Rombouts SA, Goekoop R, Stam CJ, Barkhof F, Scheltens P (2005) Delayed rather than decreased BOLD response as a marker for early Alzheimer’s disease. Neuroimage 26:1078–1085 Roy S, Rauk A (2005) Alzheimer’s disease and the ‘ABSENT’ hypothesis: mechanism for amyloid beta endothelial and neuronal toxicity. Med Hypotheses 65:123–137 Sabayan B, Jansen S, Oleksik AM, van Osch MJ, van Buchem MA, van Vliet P et al (2012) Cerebrovascular hemodynamics in Alzheimer’s disease and vascular dementia: a meta-analysis of transcranial Doppler studies. Ageing Res Rev 11:271–277 Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M et al (2014) Bapineuzumab 301 and 302 Clinical Trial Investigators. Two phase 3 trials of bapineuzumab in mild-tomoderate Alzheimer’s disease. N Engl J Med 370:322–333
Sun X, He G, Qing H, Zhou W, Dobie F, Cai F et al (2006) Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA 103:18727–18732 Valla J, Schneider L, Niedzielko T, Coon KD, Caselli R, Sabbagh MN et al (2006) Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment. Mitochondrion 6:323–330 Wang X, Su B, Fujioka H, Zhu X (2008a) 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 Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y et al (2008b) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 105:19318–19323 Xu J, Chen S, Ku G, Ahmed SH, Xu J, Chen H et al (2001) Amyloid beta peptide-induced cerebral endothelial cell death involves mitochondrial dysfunction and caspase activation. J Cereb Blood Flow Metab 21:702–710 Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 106:14670–14675
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