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The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models.
Cells. 2020 05 12; 9(5)C

Abstract

: Brains that are affected by Alzheimer's disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite.

Authors+Show Affiliations

IPMC UMR 7275 CNRS/UCA, Laboratory of Excellence DistALZ, 660 route des Lucioles 06650 Valbonne, France.IPMC UMR 7275 CNRS/UCA, Laboratory of Excellence DistALZ, 660 route des Lucioles 06650 Valbonne, France.IPMC UMR 7275 CNRS/UCA, Laboratory of Excellence DistALZ, 660 route des Lucioles 06650 Valbonne, France.IPMC UMR 7275 CNRS/UCA, Laboratory of Excellence DistALZ, 660 route des Lucioles 06650 Valbonne, France.Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, City, Missouri, 63110, USA.Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. John Cochran Veterans Affairs Medical Center, St. Louis, MO 63106, USA.Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, City, Missouri, 63110, USA.IPMC UMR 7275 CNRS/UCA, Laboratory of Excellence DistALZ, 660 route des Lucioles 06650 Valbonne, France.IPMC UMR 7275 CNRS/UCA, Laboratory of Excellence DistALZ, 660 route des Lucioles 06650 Valbonne, France.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32408680

Citation

Bécot, Anaïs, et al. "The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models." Cells, vol. 9, no. 5, 2020.
Bécot A, Pardossi-Piquard R, Bourgeois A, et al. The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models. Cells. 2020;9(5).
Bécot, A., Pardossi-Piquard, R., Bourgeois, A., Duplan, E., Xiao, Q., Diwan, A., Lee, J. M., Lauritzen, I., & Checler, F. (2020). The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models. Cells, 9(5). https://doi.org/10.3390/cells9051204
Bécot A, et al. The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models. Cells. 2020 05 12;9(5) PubMed PMID: 32408680.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models. AU - Bécot,Anaïs, AU - Pardossi-Piquard,Raphaëlle, AU - Bourgeois,Alexandre, AU - Duplan,Eric, AU - Xiao,Qingli, AU - Diwan,Abhinav, AU - Lee,Jin-Moo, AU - Lauritzen,Inger, AU - Checler,Frédéric, Y1 - 2020/05/12/ PY - 2020/04/14/received PY - 2020/04/29/revised PY - 2020/05/08/accepted PY - 2020/5/16/entrez PY - 2020/5/16/pubmed PY - 2021/2/25/medline KW - 3xTgAD mice KW - AAV8 KW - Alzheimer’s disease KW - C99 KW - TFEB KW - cathepsins KW - lysosomes KW - βCTF JF - Cells JO - Cells VL - 9 IS - 5 N2 - : Brains that are affected by Alzheimer's disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite. SN - 2073-4409 UR - https://www.unboundmedicine.com/medline/citation/32408680/The_Transcription_Factor_EB_Reduces_the_Intraneuronal_Accumulation_of_the_Beta_Secretase_Derived_APP_Fragment_C99_in_Cellular_and_Mouse_Alzheimer’s_Disease_Models_ L2 - https://www.mdpi.com/resolver?pii=cells9051204 DB - PRIME DP - Unbound Medicine ER -