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TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid β-Protein Generation in Neurons.
Neuroscience. 2019 03 15; 402:11-22.N

Abstract

Abnormalities of the autophagy-lysosomal pathway (ALP) have been implicated in the pathology of Alzheimer's disease (AD). Activation of TFEB (transcription factor EB), a master regulator of the ALP, leads to ALP facilitation. The present study sought to clarify whether TFEB-mediated ALP facilitation influences the process of amyloid β-protein (Aβ) generation in neurons. TFEB was overexpressed in mature rat primary cortical neurons via recombinant adenoviruses, without (basal conditions) or with co-overexpression of wild-type amyloid precursor protein (APP) or its β-C-terminal fragment (β-CTF). We confirmed that TFEB overexpression upregulated the lysosomal proteins, cathepsin D and LAMP-1. In TFEB-expressing neurons, protein levels of ADAM10 were profoundly increased, whereas those of APP, BACE1, or γ-secretase complex proteins were unaffected. However, TFEB did not affect ADAM10 mRNA levels. TFEB overexpression had different effects on Aβ production depending on the expression level of APP or β-CTF: TFEB slightly decreased Aβ secretion under basal conditions; clearly increased α-CTF levels and marginally increased β-CTF levels with modest increases in secreted Aβ in APP-expressing neurons; and caused a remarkable increase in β-CTF levels with a significant increase in secreted Aβ in β-CTF-expressing neurons. Inhibition of proteasomes, but not lysosomes, markedly increased β-CTF levels in β-CTF-expressing neurons. These results collectively indicate that TFEB modulates Aβ production not only by increasing α-secretase processing of APP through ADAM10 upregulation but also by augmenting β-CTF levels possibly via altered proteasome-mediated catabolism. Thus, TFEB-mediated ALP enhancement appears to have dual, but opposite, effects on Aβ production in neurons.

Authors+Show Affiliations

Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan; Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan.Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan.Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, Florida 34987, United States.Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan. Electronic address: araki@ncnp.go.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30677488

Citation

Yamamoto, Fumiko, et al. "TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid β-Protein Generation in Neurons." Neuroscience, vol. 402, 2019, pp. 11-22.
Yamamoto F, Taniguchi K, Mamada N, et al. TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid β-Protein Generation in Neurons. Neuroscience. 2019;402:11-22.
Yamamoto, F., Taniguchi, K., Mamada, N., Tamaoka, A., Kametani, F., Lakshmana, M. K., & Araki, W. (2019). TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid β-Protein Generation in Neurons. Neuroscience, 402, 11-22. https://doi.org/10.1016/j.neuroscience.2019.01.010
Yamamoto F, et al. TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid β-Protein Generation in Neurons. Neuroscience. 2019 03 15;402:11-22. PubMed PMID: 30677488.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid β-Protein Generation in Neurons. AU - Yamamoto,Fumiko, AU - Taniguchi,Kaori, AU - Mamada,Naomi, AU - Tamaoka,Akira, AU - Kametani,Fuyuki, AU - Lakshmana,Madepalli K, AU - Araki,Wataru, Y1 - 2019/01/21/ PY - 2018/08/18/received PY - 2019/01/08/revised PY - 2019/01/11/accepted PY - 2019/1/25/pubmed PY - 2019/6/22/medline PY - 2019/1/25/entrez KW - ADAM10 KW - Alzheimer KW - Aβ KW - TFEB KW - autophagy-lysosomal pathway KW - neuron SP - 11 EP - 22 JF - Neuroscience JO - Neuroscience VL - 402 N2 - Abnormalities of the autophagy-lysosomal pathway (ALP) have been implicated in the pathology of Alzheimer's disease (AD). Activation of TFEB (transcription factor EB), a master regulator of the ALP, leads to ALP facilitation. The present study sought to clarify whether TFEB-mediated ALP facilitation influences the process of amyloid β-protein (Aβ) generation in neurons. TFEB was overexpressed in mature rat primary cortical neurons via recombinant adenoviruses, without (basal conditions) or with co-overexpression of wild-type amyloid precursor protein (APP) or its β-C-terminal fragment (β-CTF). We confirmed that TFEB overexpression upregulated the lysosomal proteins, cathepsin D and LAMP-1. In TFEB-expressing neurons, protein levels of ADAM10 were profoundly increased, whereas those of APP, BACE1, or γ-secretase complex proteins were unaffected. However, TFEB did not affect ADAM10 mRNA levels. TFEB overexpression had different effects on Aβ production depending on the expression level of APP or β-CTF: TFEB slightly decreased Aβ secretion under basal conditions; clearly increased α-CTF levels and marginally increased β-CTF levels with modest increases in secreted Aβ in APP-expressing neurons; and caused a remarkable increase in β-CTF levels with a significant increase in secreted Aβ in β-CTF-expressing neurons. Inhibition of proteasomes, but not lysosomes, markedly increased β-CTF levels in β-CTF-expressing neurons. These results collectively indicate that TFEB modulates Aβ production not only by increasing α-secretase processing of APP through ADAM10 upregulation but also by augmenting β-CTF levels possibly via altered proteasome-mediated catabolism. Thus, TFEB-mediated ALP enhancement appears to have dual, but opposite, effects on Aβ production in neurons. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/30677488/TFEB_mediated_Enhancement_of_the_Autophagy_lysosomal_Pathway_Dually_Modulates_the_Process_of_Amyloid_β_Protein_Generation_in_Neurons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(19)30030-2 DB - PRIME DP - Unbound Medicine ER -