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. 2018 Sep 3;215(9):2355–2377. doi: 10.1084/jem.20172158

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© 2018 Martini-Stoica et al.

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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Figure 1. — TFEB activity is enhanced in response to AD/tauopathy disease progression. (A) Human brain TFEB transcript levels stratified by clinical assessment of cognition from the MSSM cohorts in the AMP-AD reprocessed RNA-seq project (parahippocampal gyrus; n = 130). The three dementia groups are defined based on CERAD score (CDR): CDR = 0 is NCI, CDR = 0.5 is MCI, CDR ≥1 is Dementia. Performed once. (B) Human brain TFEB transcript levels stratified by Braak score (1–6) from the MSSM cohorts in AMP-AD reprocessed RNA-seq project (parahippocampal gyrus; n = 130). Spearman’s correlation coefficient is computed between the expression and dementia group status (A) or Braak score (B) and P value show the significance of the observed correlation computed using the asymptotic t approximation algorithm. Performed once. (C) qRT-PCR analysis of the transcriptional levels of TFEB and its lysosomal target genes in the frontal cortex of FTD or normal human subjects. n = 15 FTD, 8 normal cases. Student’s t test, experiments technically replicated twice. (D and E) Representative Western blot with quantitation (E) of TFEB and its lysosomal targets LAMP1 and CTSD, as well as phospho tau levels indicated by phospho tau antibody PHF1 in normal versus FTD human subjects. n = 15 FTD, 9 normal cases. #P = 0.14. Student’s t test; experiment technically replicated twice. (F) GSEA of transcriptomic changes in the brains of 4-mo-old wild-type versus rTg4510 mice. The left panel shows enrichment of TFEB transcriptional targets (ES: 0.36, P value: 0.0096), while the right panel demonstrates enrichment of TFEB lysosomal transcriptional targets (ES: 0.72; P value: <0.001). n = 4/group. Performed once. (G) qRT-PCR of TFEB regulated lysosomal genes in astrocytes from 4.5-mo-old wild-type versus rTg4510 mice. n = 8/group. Student’s t test; pooled from three independent experiments. CTSA, Cathepsin A; CTSB, Cathepsin B. (H and I) Representative confocal images of FLAG (green) and DAPI (blue) staining in the forebrain of P3 AAV-GFAP-TFEB injected wild-type or rTg4510 mice at 4 mo of age with quantification (I). Bar, 10 µm. n = 5/group with 5 images/animal; Student’s t test, representative of two independently performed experiments. Molecular mass indicated in kilodaltons. Error bars designate SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001.