Amyloid-β Causes Mitochondrial Dysfunction via a Ca 2+ -Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells
Restricted accessResearch articleFirst published online May 5, 2020
Amyloid-β Causes Mitochondrial Dysfunction via a Ca 2+ -Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells
Cerebrovascular pathology is pervasive in Alzheimer’s disease (AD), yet it is unknown whether cerebrovascular dysfunction contributes to the progression or etiology of AD. In human subjects and in animal models of AD, cerebral hypoperfusion and hypometabolism are reported to manifest during the early stages of the disease and persist for its duration. Amyloid-β is known to cause cellular injury in both neurons and endothelial cells by inducing the production of reactive oxygen species and disrupting intracellular Ca2+ homeostasis. We present a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which is driven by increased mitochondrial Ca2+ uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. These observations provide a mechanism for the mitochondrial deficits that contribute to cerebrovascular dysfunction in patients with AD.
JansonCG (2015) AD and CAA: Independent risk factors for dementia. Sci Transl Med7, 318ec214.
4.
DeSimoneCV, Graff-RadfordJ, El-HarasisMA, RabinsteinAA, AsirvathamSJ, HolmesDR (2017) Cerebral amyloid angiopathy: Diagnosis, clinical implications, and management strategies in atrial fibrillation. J Am Coll Cardiol70, 1173–1182.
5.
VintersHV (1987) Cerebral amyloid angiopathy. A critical review. Stroke18, 311–324.
6.
HanBH, ZhouM-L, JohnsonAW, SinghI, LiaoF, VellimanaAK, NelsonJW, MilnerE, CirritoJR, BasakJ, YooM, DietrichHH, HoltzmanDM, ZipfelGJ (2015) Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice. Proc Natl Acad Sci U S A112, E881–E890.
7.
de la TorreJC (2004) Alzheimer’s disease is a vasocognopathy: A new term to describe its nature. Neurol Res26, 517–524.
8.
BrundelM, de BresserJ, van DillenJJ, KappelleLJ, BiesselsGJ (2012) Cerebral microinfarcts: A systematic review of neuropathological studies. J Cereb Blood Flow Metab32, 425–436.
9.
BrundelM, HeringaSM, de BresserJ, KoekHL, ZwanenburgJJM, Jaap KappelleL, LuijtenPR, BiesselsGJ (2012) High prevalence of cerebral microbleeds at 7Tesla MRI in patients with early Alzheimer’s disease. J Alzheimers Dis31, 259–263.
10.
ChiN-F, ChienL-N, KuH-L, HuC-J, ChiouH-Y (2013) Alzheimer disease and risk of stroke: A population-based cohort study. Neurology80, 705–711.
11.
PurandareN, BurnsA (2009) Cerebral emboli in the genesis of dementia. J Neurol Sci283, 17–20.
12.
TolppanenA-M, LavikainenP, SolomonA, KivipeltoM, SoininenH, HartikainenS (2013) Incidence of stroke in people with Alzheimer disease: A national register-based approach. Neurology80, 353–358.
13.
de la TorreJC (2010) Vascular risk factor detection and control may prevent Alzheimer’s disease. Ageing Res Rev9, 218–225.
14.
JellingerKA (2010) Prevalence and impact of cerebrovascular lesions in Alzheimer and lewy body diseases. Neurodegener Dis7, 112–115.
15.
KalariaRN (2010) Vascular basis for brain degeneration: Faltering controls and risk factors for dementia. Nutr Rev68(Suppl 2), S74–87.
16.
YaoJ, IrwinRW, ZhaoL, NilsenJ, HamiltonRT, BrintonRD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A106, 14670–14675.
ManczakM, CalkinsMJ, ReddyPH (2011) Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer’s disease: Implications for neuronal damage. Hum Mol Genet20, 2495–2509.
21.
WangW, YinJ, MaX, ZhaoF, SiedlakSL, WangZ, TorresS, FujiokaH, XuY, PerryG, ZhuX (2017) Inhibition of mitochondrial fragmentation protects against Alzheimer’s disease in rodent model. Hum Mol Genet26, 4118–4131.
22.
DuH, GuoL, YanS, SosunovAA, McKhannGM, YanSS (2010) Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. Proc Natl Acad Sci U S A107, 18670–18675.
23.
ChoD-H, NakamuraT, FangJ, CieplakP, GodzikA, GuZ, LiptonSA (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science324, 102–105.
24.
ParkL, AnratherJ, ForsterC, KazamaK, CarlsonGA, IadecolaC (2004) Aβ-induced vascular oxidative stress and attenuation of functional hyperemia in mouse somatosensory cortex. J Cereb Blood Flow Metab24, 334–342.
25.
DrummondGR, SelemidisS, GriendlingKK, SobeyCG (2011) Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov10, 453–471.
26.
MillerAA, DrummondGR, SchmidtHHHW, SobeyCG (2005) NADPH oxidase activity and function are profoundly greater in cerebral versus systemic arteries. Circ Res97, 1055–1062.
27.
ParkL, AnratherJ, GirouardH, ZhouP, IadecolaC (2007) Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab27, 1908–1918.
28.
ParkL, AnratherJ, ZhouP, FrysK, PitstickR, YounkinS, CarlsonGA, IadecolaC (2005) NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci25, 1769–1777.
29.
LamplT, CrumJA, DavisTA, MilliganC, Del Gaizo MooreV (2015) Isolation and functional analysis of mitochondria from cultured cells and mouse tissue. J Vis Exp, doi: 10.3791/52076.
TakumaH, TomiyamaT, KuidaK, MoriH (2004) Amyloid beta peptide-induced cerebral neuronal loss is mediated by caspase-3 in vivo. J Neuropathol Exp Neurol63, 255–261.
32.
BastianettoS, RamassamyC, DoréS, ChristenY, PoirierJ, QuirionR (2000) The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci12, 1882–1890.
33.
MookerjeeSA, GerencserAA, NichollsDG, BrandMD (2017) Quantifying intracellular rates of glycolytic and oxidative ATP production and consumption using extracellular flux measurements. J Biol Chem292, 7189–7207.
34.
ZeidlerJD, Fernandes-SiqueiraLO, CarvalhoAS, Cararo-LopesE, DiasMH, KetzerLA, GalinaA, Da PoianAT (2017) Short-term starvation is a strategy to unravel the cellular capacity of oxidizing specific exogenous/endogenous substrates in mitochondria. J Biol Chem292, 14176–14187.
35.
BraceLE, VoseSC, StanyaK, GathunguRM, MarurVR, LongchampA, Treviño-VillarrealH, MejiaP, VargasD, InouyeK, BronsonRT, LeeC-H, NeilanE, KristalBS, MitchellJR (2016) Increased oxidative phosphorylation in response to acute and chronic DNA damage. NPJ Aging Mech Dis2, 16022.
36.
YajimaD, MotaniH, HayakawaM, SatoY, SatoK, IwaseH (2009) The relationship between cell membrane damage and lipid peroxidation under the condition of hypoxia-reoxygenation: Analysis of the mechanism using antioxidants and electron transport inhibitors. Cell Biochem Funct27, 338–343.
37.
JarmuszkiewiczW, Woyda-PloszczycaA, KozielA, MajerczakJ, ZoladzJA (2015) Temperature controls oxidative phosphorylation and reactive oxygen species production through uncoupling in rat skeletal muscle mitochondria. Free Radic Biol Med83, 12–20.
38.
DownsCA, HeckathornSA (1998) The mitochondrial small heat-shock protein protects NADH: Ubiquinone oxidoreductase of the electron transport chain during heat stress in plants. FEBS Lett430, 246–250.
PilchovaI, KlacanovaK, TatarkovaZ, KaplanP, RacayP (2017) The involvement of Mg 2+ in regulation of cellular and mitochondrial functions. Oxid Med Cell Longev2017, 1–8.
QuintanaDD, GarciaJA, SarkarSN, JunS, Engler-ChiurazziEB, RussellAE, CavendishJZ, SimpkinsJW (2019) Hypoxia-reoxygenation of primary astrocytes results in a redistribution of mitochondrial size and mitophagy. Mitochondrion47, 244–255.
43.
WangX, SuB, SiedlakSL, MoreiraPI, FujiokaH, WangY, CasadesusG, ZhuX (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A105, 19318–19323.
YouleRJ, van der BliekAM (2012) Mitochondrial fission, fusion, and stress. Science337, 1062–1065.
48.
XieH, GuanJ, BorrelliLA, XuJ, Serrano-PozoA, BacskaiBJ (2013) Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model. J Neurosci33, 17042–17051.
49.
GillardonF, RistW, KussmaulL, VogelJ, BergM, DanzerK, KrautN, HengererB (2007) Proteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque deposition. Proteomics7, 605–616.
50.
LaFerlaFM (2002) Calcium dyshomeostasis and intracellular signaling in Alzheimer’s disease. Nat Rev Neurosci3, 862–872.
51.
BrownGC, Lakin-ThomasPL, BrandMD (1990) Control of respiration and oxidative phosphorylation in isolated rat liver cells. Eur J Biochem192, 355–362.
52.
AinscowEK, BrandMD (1999) Top-down control analysis of ATP turnover, glycolysis and oxidative phosphorylation in rat hepatocytes. Eur J Biochem263, 671–685.
53.
YadavaN, NichollsDG (2007) Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity after partial respiratory inhibition of mitochondrial complex I with rotenone. J Neurosci27, 7310–7317.
54.
ChoiSW, GerencserAA, NichollsDG (2009) Bioenergetic analysis of isolated cerebrocortical nerve terminals on a microgram scale: Spare respiratory capacity and stochastic mitochondrial failure. J Neurochem109, 1179–1191.
55.
HansfordRG, ChappellJB (1967) The effect of Ca2+ on the oxidation of glycerol phosphate by blowfly flight-muscle mitochondria. Biochem Biophys Res Commun27, 686–692.
56.
DentonRM, RandlePJ, MartinBR (1972) Stimulation by calcium ions of pyruvate dehydrogenase phosphate phosphatase. Biochem J128, 161–163.
57.
McCormackJG, DentonRM (1979) The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex. Biochem J180, 533–544.
58.
McCormackJG, HalestrapAP, DentonRM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev70, 391–425.
59.
KroemerG, ReedJC (2000) Mitochondrial control of cell death. Nat Med6, 513–519.
OrreniusS, ZhivotovskyB, NicoteraP (2003) Regulation of cell death: The calcium–apoptosis link. Nat Rev Mol Cell Biol4, 552–565.
62.
ChouchaniET, PellVR, JamesAM, WorkLM, Saeb-ParsyK, FrezzaC, KriegT, MurphyMP (2016) A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury. Cell Metab23, 254–263.
63.
BodeDC, BakerMD, VilesJH (2017) Ion channel formation by amyloid-β42 oligomers but not amyloid-β40 in cellular membranes. J Biol Chem292, 1404–1413.
64.
DemuroA, MinaE, KayedR, MiltonSC, ParkerI, GlabeCG (2005) Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem280, 17294–17300.
65.
HoytKR, ArdenSR, AizenmanE, ReynoldsIJ (1998) Reverse Na+/Ca2+ exchange contributes to glutamate-induced intracellular Ca2+ concentration increases in cultured rat forebrain neurons. Mol Pharmacol53, 742–749.
66.
KiedrowskiL (1999) N-methyl-D-aspartate excitotoxicity: Relationships among plasma membrane potential, Na+/Ca2+ exchange, mitochondrial Ca2+ overload, and cytoplasmic concentrations of Ca2+ H+ and+. Mol Pharmacol56, 619–632.
67.
GriffithsEJ (1999) Reversal of mitochondrial Na/Ca exchange during metabolic inhibition in rat cardiomyocytes. FEBS Lett453, 400–404.
68.
SmetsI, CaplanusiA, DespaS, MolnarZ, RaduM, VandeVenM, AmelootM, SteelsP (2004) Ca2+ uptake in mitochondria occurs via the reverse action of the Na+/Ca2+ exchanger in metabolically inhibited MDCK cells. Am J Physiol Renal Physiol286, F784–F794.
69.
BrustovetskyT, BrittainMK, SheetsPL, CumminsTR, PinelisV, BrustovetskyN (2011) KB-R7943, an inhibitor of the reverse Na+/Ca2+ exchanger, blocks N-methyl-D-aspartate receptor and inhibits mitochondrial complex i. Br J Pharmacol162, 255–270.
70.
RizzutoR, PintonP, CarringtonW, FayFS, FogartyKE, LifshitzLM, TuftRA, PozzanT (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science280, 1763–1766.
71.
BartolomeF, de la CuevaM, PascualC, AntequeraD, FernandezT, GilC, MartinezA, CarroE (2018) Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition. Alzheimers Res Ther10, 24.
AlmeidaA, MedinaJM (1998) A rapid method for the isolation of metabolically active mitochondria from rat neurons and astrocytes in primary culture. Brain Res Protoc2, 209–214.
74.
JežekJ, CooperKF, StrichR (2018) Reactive oxygen species and mitochondrial dynamics: The yin and yang of mitochondrial dysfunction and cancer progression. Antioxidants (Basel)7, E13.
HungCH-L, ChengSS-Y, CheungY-T, WuwongseS, ZhangNQ, HoY-S, LeeSM-Y, ChangRC-C (2018) A reciprocal relationship between reactive oxygen species and mitochondrial dynamics in neurodegeneration. Redox Biol14, 7–19.
