Journal: bioRxiv

Article Title: Rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral AAV-mediated expression of brain-penetrant progranulin

doi: 10.1101/2023.07.14.549089

Figure Lengend Snippet: ( A ) Schematics of AAV treatment and sample collection in the Grn x Tmem106b double knockout (DKO) AAV(L):bPGRN treatment study. ( B-D ) hPGRN levels in plasma (left, n=7/group; 6, 10 and 15-week-old), liver (middle, n=4-6/group; 15-week-old) and brain (right, n=7/group; 15-week-old) following AAV(L):bPGRN treatment in mice as assessed by ELISA. ( E ) Longitudinal assessment of rotarod performance following treatment. ( F ) Quantification of the flipping test based on a scoring system (n=7/group). ( G ) Quantification of the hind limb clasping test based on a scoring system (n=7/group). Data is depicted as mean ± standard deviation (SD), data points represent individual animals. For E, overall comparison was performed by two-way ANOVA with Tukey’s multiple comparison. Individual groups in E were compared using two-tailed student’s t-test. For F and G, one-way ANOVA with Tukey’s multiple comparison was performed. ns p > 0.05, **p < 0.01, ****p < 0.0001.

Article Snippet: Human PGRN levels in Grn KO mice were measured using the DuoSet ELISA kit (R&D DY2420) as previously described ( ).

Techniques: Double Knockout, Clinical Proteomics, Enzyme-linked Immunosorbent Assay, Standard Deviation, Comparison, Two Tailed Test

Journal: bioRxiv

Article Title: Rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral AAV-mediated expression of brain-penetrant progranulin

doi: 10.1101/2023.07.14.549089

Figure Lengend Snippet: ( A ) mPGRN levels in plasma following AAV(L):bPGRN treatment in WT and DKO mice as assessed by ELISA (n=3-7/group). ( B ) mPGRN levels in brain following treatment as assessed by Western blot (n=3/group). ( C ) Quantification of mPGRN levels in B normalized to WT (n=3/group). Data is depicted as mean ± SD, data points represent individual animals. For statistical analysis, one-way ANOVA with Tukey’s multiple comparison was performed. ns p > 0.05.

Article Snippet: Human PGRN levels in Grn KO mice were measured using the DuoSet ELISA kit (R&D DY2420) as previously described ( ).

Techniques: Clinical Proteomics, Enzyme-linked Immunosorbent Assay, Western Blot, Comparison

Journal: bioRxiv

Article Title: Rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral AAV-mediated expression of brain-penetrant progranulin

doi: 10.1101/2023.07.14.549089

Figure Lengend Snippet: ( A ) Heatmap depiction of transcriptional changes in 12-month-old Grn KO mice following 31 weeks of AAV(L):bPGRN treatment. Columns represent individual animals. Plotted values are log2 transformed. ( B ) Representative immunofluorescence images of the thalamus showing Iba1 + and Cd68 + cells (scalebar = 20 µm). ( C ) Regional quantification of Cd68 and Iba1 in whole hemispheres (left), cortex (middle left), hippocampus (middle right) and thalamus (right). ( D ) ELISA-quantified mTrem2 levels in brain (left), liver (middle) and plasma (right) in 12-month-old Grn KO mice following 31 weeks of AAV(L):bPGRN treatment. n=5-6/group. Data is depicted as mean ± SEM ns p > 0.05, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Article Snippet: Human PGRN levels in Grn KO mice were measured using the DuoSet ELISA kit (R&D DY2420) as previously described ( ).

Techniques: Transformation Assay, Immunofluorescence, Enzyme-linked Immunosorbent Assay, Clinical Proteomics

Journal: bioRxiv

Article Title: Rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral AAV-mediated expression of brain-penetrant progranulin

doi: 10.1101/2023.07.14.549089

Figure Lengend Snippet: ( A ) UMAP depiction of full transcript profile comparing untreated and AAV(L):bPGRN-treated WT and DKO mice (n=7/group). ( B ) Heatmap showing the top 222 differentially expressed genes in DKO mice and correction with AAV(L):bPGRN with a false discovery rate (FDR) < 5% and at least a 20% change comparing WT and DKO as well as DKO AAV and DKO. Plotted values are log2 transformed fold changes (FC) (n=7/group). ( C ) Transcriptional changes in genes linked to lysosomal function (n=7/group). ( D ) Representative immunofluorescence images of the thalamus of WT and DKO mice after treatment showing Iba1 + , Gfap + and Cd68 + cells (scalebar = 10 µm). ( E ) Quantification of the Gfap + , Iba1 + and Iba + /Cd68 + area in whole brain hemispheres (n=3/group). ( F ) mTrem2 levels in plasma (left, n=7/group), brain (middle, n=5-7/group) and liver (right, n=3/group) of WT and DKO mice after treatment at the end of the study as assessed by ELISA. C, E, F: Data is depicted as mean ± SD, data points represent individual animals. For statistical analysis, one-way ANOVA with Tukey’s multiple comparison was performed. ns p > 0.05, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Article Snippet: Human PGRN levels in Grn KO mice were measured using the DuoSet ELISA kit (R&D DY2420) as previously described ( ).

Techniques: Transformation Assay, Immunofluorescence, Clinical Proteomics, Enzyme-linked Immunosorbent Assay, Comparison