To investigate whether transcriptional factor EB (TFEB) participates in amyloid-β1–42 (Aβ1–42)-induced pathogenesis of Alzheimer's disease (AD) and its underlying mechanisms. Three-month-old and 8-month-old transgenic APP/PS1 AD mice and age-matched wild mice were used in this study. We found that the 8-month-old AD animals presented significantly higher deposition of Aβ1–42 and expression of TFEB and its targeted proteins, such as LAMP-1 and cathepsin D, and autophagy-associated LC3-II and p62 in brain tissues than in others. In an in vitro study, TFEB overexpression rescued autophagic flux that blocked by Aβ1–42 and the degradation of the absorbed Aβ1–42, relieved Aβ1–42-mediated induction of overloaded autophagy. In addition, TFEB overexpression enhanced cathepsin D expression and activity, restored Aβ1–42-disturbed acid environment of lysosome, and promoted the fusion of autophagosomes with lysosomes. Furthermore, TFEB upregulation reduced Aβ1–42-induced production of malondialdehyde, oxidative carbonyl proteins, and reactive oxygen species (ROS) and cell apoptosis mainly dependent on the removal of Aβ1–42 by the autophagy-lysosome pathway. TFEB overexpression alleviated AD progression by reducing Aβ accumulation through regulating the autophagy-lysosome pathway and reducing Aβ-induced ROS production and cell apoptosis.
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References
1.
AnekondaT.S., WadsworthT.L., SabinR., FrahlerK., HarrisC., PetrikoB., et al. (2011). Phytic acid as a potential treatment for Alzheimer's pathology: evidence from animal and in vitro models. J Alzheimers Dis, 23, 21–35.
2.
BondaD.J., LeeH.-P., LeeH.-G., FriedlichA.L., PerryG., ZhuX., et al. (2010). Novel therapeutics for Alzheimer's disease: an update. Curr Opin Drug Discov Dev, 13, 235.
3.
ChuC., ZhangX., MaW., LiL., WangW., ShangL., et al. (2013). Induction of autophagy by a novel small molecule improves abeta pathology and ameliorates cognitive deficits. PLoS One, 8, e65367.
4.
FortunatoF., and KroemerG. (2009). Impaired autophagosome-lysosome fusion in the pathogenesis of pancreatitis. Autophagy, 5, 850–853.
5.
HebertS.S., HorreK., NicolaiL., PapadopoulouA.S., MandemakersW., SilahtarogluA.N., et al. (2008). Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A, 105, 6415–6420.
6.
HettiarachchiN., DallasM., Al-OwaisM., GriffithsH., HooperN., ScraggJ., et al. (2014). Heme oxygenase-1 protects against Alzheimer's amyloid-beta(1–42)-induced toxicity via carbon monoxide production. Cell Death Dis, 5, e1569.
7.
JankowskyJ.L., FadaleD.J., AndersonJ., XuG.M., GonzalesV., JenkinsN.A., et al. (2004). Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet, 13, 159–170.
8.
LeeS.-J., LiyanageU., BickelP.E., XiaW., LansburyP.T., and KosikK.S. (1998). A detergent-insoluble membrance compartment contains Aβ in vivo. Nat Med, 4, 730–734.
9.
LingD., MagallanesM., and SalvaterraP.M. (2014). Accumulation of amyloid-like Abeta1-42 in AEL (autophagy-endosomal-lysosomal) vesicles: potential implications for plaque biogenesis. ASN Neuro, 6, pii: e00139, doi: 10.1042/AN20130044.
10.
LuoS., and WehrN.B. (2009). Protein carbonylation: avoiding pitfalls in the 2, 4-dinitrophenylhydrazine assay. Redox Rep, 14, 159–166.
11.
MajumderS., RichardsonA., StrongR., and OddoS. (2011). Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One, 6, e25416.
12.
MizushimaN., LevineB., CuervoA.M., and KlionskyD.J. (2008). Autophagy fights disease through cellular self-digestion. Nature, 451, 1069–1075.
NixonR.A., and YangD.-S. (2011). Autophagy failure in Alzheimer's disease-locating the primary defect. Neurobiol Dis, 43, 38–45.
15.
PatsoukisN., and GeorgiouC.D. (2004). Determination of the thiol redox state of organisms: new oxidative stress indicators. Anal Bioanal Chem, 378, 1783–1792.
16.
PolitoV.A., LiH., Martini-StoicaH., WangB., YangL., XuY., et al. (2014). Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol Med, 6, 1142–1160.
17.
Roczniak-FergusonA., PetitC.S., FroehlichF., QianS., KyJ., AngarolaB., et al. (2012). The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal, 5, ra42.
18.
SatohJ. (2012). Molecular network of microRNA targets in Alzheimer's disease brains. Exp Neurol, 235, 436–446.
19.
SettembreC., Di MaltaC., PolitoV.A., Garcia ArencibiaM., VetriniF., ErdinS., et al. (2011). TFEB links autophagy to lysosomal biogenesis. Science, 332, 1429–1433.
20.
SettembreC., ZoncuR., MedinaD.L., VetriniF., ErdinS., HuynhT., et al. (2012). A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J, 31, 1095–1108.
21.
Turunc BayrakdarE., UyanikgilY., KanitL., KoyluE., and YalcinA. (2014). Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Abeta(1–42)-induced rat model of Alzheimer's disease. Free Radic Res, 48, 146–158.
22.
WangW.X., HuangQ., HuY., StrombergA.J., and NelsonP.T. (2011). Patterns of microRNA expression in normal and early Alzheimer's disease human temporal cortex: white matter versus gray matter. Acta Neuropathol, 121, 193–205.
23.
WangW.-X., RajeevB.W., StrombergA.J., RenN., TangG., HuangQ., et al. (2008). The expression of microRNA miR-107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of β-site amyloid precursor protein-cleaving enzyme 1. J Neurosci, 28, 1213–1223.
24.
WeihlC.C. (2013). Monitoring autophagy in the treatment of protein aggregate diseases: steps toward identifying autophagic biomarkers. Neurotherapeutics, 10, 383–390.
25.
WongE., and CuervoA.M. (2010). Autophagy gone awry in neurodegenerative diseases. Nat Neurosci, 13, 805–811.
YangD.S., StavridesP., SaitoM., KumarA., Rodriguez-NavarroJ.A., PawlikM., et al. (2014). Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits. Brain, 137, 3300–3318.
28.
ZhaoT., HuangX., HanL., WangX., ChengH., ZhaoY., et al. (2012). Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes. J Biol Chem, 287, 23615–23625.
29.
ZhouJ., TanS.H., NicolasV., BauvyC., YangN.D., ZhangJ., et al. (2013). Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion. Cell Res, 23, 508–523.
30.
ZhuX., ChenC., YeD., GuanD., YeL., JinJ., et al. (2012). Diammonium glycyrrhizinate upregulates PGC-1alpha and protects against Abeta1-42-induced neurotoxicity. PLoS One, 7, e35823.
