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p301l mutant human tau transgenic mouse model of tauopathy rtg4510 (Jackson Laboratory)

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Jackson Laboratory p301l mutant human tau transgenic mouse model of tauopathy rtg4510
P301l Mutant Human Tau Transgenic Mouse Model Of Tauopathy Rtg4510, supplied by Jackson Laboratory, used in various techniques. Bioz Stars score: 90/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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p301l mutant human tau transgenic mouse model of tauopathy rtg4510 - by Bioz Stars, 2026-03

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Stimulation of anaplerotic metabolism enhances oxidative phosphorylation (OXPHOS) activity in tauopathy neurons. (A) Schematic depicting glutamine-stimulated anaplerotic metabolism to enhance OXPHOS through the conversion of Gln into α-ketoglutarate, an intermediate of the TCA cycle. OXPHOS: oxidative phosphorylation; TCA: tricarboxylic acid. (B) Analysis of the COX activity of mitochondria that were freshly isolated from days in vitro (DIV)10-12 primary cortical neuron cultures derived from non-transgenic (Tg) and MAPT/Tau P301S Tg (PS19) mouse brains. Results in non-Tg and MAPT/Tau P301S Tg neurons with Gln (10 mM) were normalized to those in control neurons in the absence of Gln, respectively. Data were quantified from 7-8 animal-derived neuron cultures from three independent dissections. (C) Relative abundance of alpha-ketoglutarate and other TCA metabolites in MAPT/Tau P301S Tg neurons with and without Gln supplementation. (D-F) Representative images (D, E) and quantitative analysis (F) of mitochondrial ATP levels indicated by mitAT1.03 in DIV10-12 non-Tg and MAPT/Tau P301S Tg neurons with and without 7 h Gln (10 mM) treatment. The YFP:CFP ratios of the somatic and axonal mitochondria in non-Tg and MAPT/Tau P301S Tg neurons were normalized to those in control neurons without Gln supplementation, respectively. (G-H) Representative images (G) and quantitative analysis (H) of the densities of endogenous HSPD1-labeled mitochondria and SYP (synaptophysin)-marked presynaptic terminals in the axonal processes of non-Tg neurons or MAPT/Tau P301S neurons at DIV12-14 with and without 24 h 10 mM Gln treatment. Results in Gln-treated non-Tg and MAPT/Tau P301S axons were normalized to those in control axons without Gln, respectively. Data were collected from a total number of neuronal soma (n) or axons (v) (F) or axons (n) (H) indicated in parentheses from five independent experimental repeats or were quantified from five independent repeats (B and C). Data were expressed as the mean ± SEM with dots as individual values and analyzed with mann-whitney U test (B and C) or two-sided unpaired Student’s t -test (F and H). Scale bars: 10 µm.

Journal: Autophagy

Article Title: Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons

doi: 10.1080/15548627.2024.2392408

Figure Lengend Snippet: Stimulation of anaplerotic metabolism enhances oxidative phosphorylation (OXPHOS) activity in tauopathy neurons. (A) Schematic depicting glutamine-stimulated anaplerotic metabolism to enhance OXPHOS through the conversion of Gln into α-ketoglutarate, an intermediate of the TCA cycle. OXPHOS: oxidative phosphorylation; TCA: tricarboxylic acid. (B) Analysis of the COX activity of mitochondria that were freshly isolated from days in vitro (DIV)10-12 primary cortical neuron cultures derived from non-transgenic (Tg) and MAPT/Tau P301S Tg (PS19) mouse brains. Results in non-Tg and MAPT/Tau P301S Tg neurons with Gln (10 mM) were normalized to those in control neurons in the absence of Gln, respectively. Data were quantified from 7-8 animal-derived neuron cultures from three independent dissections. (C) Relative abundance of alpha-ketoglutarate and other TCA metabolites in MAPT/Tau P301S Tg neurons with and without Gln supplementation. (D-F) Representative images (D, E) and quantitative analysis (F) of mitochondrial ATP levels indicated by mitAT1.03 in DIV10-12 non-Tg and MAPT/Tau P301S Tg neurons with and without 7 h Gln (10 mM) treatment. The YFP:CFP ratios of the somatic and axonal mitochondria in non-Tg and MAPT/Tau P301S Tg neurons were normalized to those in control neurons without Gln supplementation, respectively. (G-H) Representative images (G) and quantitative analysis (H) of the densities of endogenous HSPD1-labeled mitochondria and SYP (synaptophysin)-marked presynaptic terminals in the axonal processes of non-Tg neurons or MAPT/Tau P301S neurons at DIV12-14 with and without 24 h 10 mM Gln treatment. Results in Gln-treated non-Tg and MAPT/Tau P301S axons were normalized to those in control axons without Gln, respectively. Data were collected from a total number of neuronal soma (n) or axons (v) (F) or axons (n) (H) indicated in parentheses from five independent experimental repeats or were quantified from five independent repeats (B and C). Data were expressed as the mean ± SEM with dots as individual values and analyzed with mann-whitney U test (B and C) or two-sided unpaired Student’s t -test (F and H). Scale bars: 10 µm.

Article Snippet: MAPT/Tau P301L (rTg4510) and MAPT/Tau P301S (PS19) mouse lines [ , ] were purchased from the Jackson Laboratory.

Techniques: Activity Assay, Isolation, In Vitro, Derivative Assay, Transgenic Assay, Control, Labeling, MANN-WHITNEY

Anaplerotic enhancement of OXPHOS in tauopathy neurons enhances MAPT/tau clearance by increasing autophagosome/autophagic vacuole (AV) biogenesis. (A and B) Representative blots (A) and quantitative analysis (B) of autophagy and MAPT/tau protein levels in MAPT/Tau P301S Tg neurons at DIV12-14 treated 24 h with 10 µg/ml CHX or CHX and 10 mM Gln. The protein levels were normalized to STX1 (syntaxin 1) and to those of control MAPT/Tau P301S Tg neurons in the absence of Gln, respectively. CHX: cycloheximide. (C-D) Representative blots (C) and quantitative analysis (D) of monomeric and oligomeric MAPT/tau levels revealed by a non-reducing gel in DIV12-14 MAPT/Tau P301S Tg neurons incubated 24 h with CHX, CHX and Gln, or CHX, Gln, and LIs (20 µm pepstatin a and 20 µm E-64d). The protein levels were normalized to those of MAPT/Tau P301S Tg neurons with CHX alone. LIs: lysosomal inhibitors. (E and F) Representative images (E) and quantitative analysis (F) of autophagic flux in the axons of DIV10-12 MAPT/Tau P301S Tg neurons in the presence and absence of LIs (20 µm pepstatin a and 20 µm E-64d), Gln, or Gln and LIs for 24 h. The data were quantified and expressed as the number of GFP-LC3-marked AVs per 100 µm axonal length in MAPT/Tau P301S neurons. AV: autophagosome/autophagic vacuole. (G and H) Representative images (G) and quantitative analysis (H) of AV density in DIV10-12 Gln-supplemented MAPT/Tau P301S axons expressing ATG5 or ATG5 K130R in the presence and absence of 100 nM bafilomycin A 1 . Baf-A1: bafilomycin A 1 . (I-J) Representative dual-channel kymographs (I) and quantitative analysis (J) of AV motility in the axons of MAPT/Tau P301S neurons with 24 h Gln treatment. (K and L) Representative images (K) and quantitative analysis (L) of AV density in the axons of DIV10-12 control and 10 mM Gln-supplemented MAPT/Tau P301S neurons with and without 1 µm oligomycin or 100 nM antimycin A. Omy: oligomycin; AA: antimycin A. Data were quantified from five independent repeats (B and D) or were collected from the total number of neurons (n) as indicated in parentheses (F, H, J, and L) from three independent experiments. Data were expressed as the mean ± SEM and analyzed by mann-whitney U test (B), Kruskal-Wallis test with Dun’s multiple comparison post hoc test (D), or one-way ANOVA with Bonferroni’s correction (F, H, and L). Scale bars: 10 µm.

Journal: Autophagy

Article Title: Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons

doi: 10.1080/15548627.2024.2392408

Figure Lengend Snippet: Anaplerotic enhancement of OXPHOS in tauopathy neurons enhances MAPT/tau clearance by increasing autophagosome/autophagic vacuole (AV) biogenesis. (A and B) Representative blots (A) and quantitative analysis (B) of autophagy and MAPT/tau protein levels in MAPT/Tau P301S Tg neurons at DIV12-14 treated 24 h with 10 µg/ml CHX or CHX and 10 mM Gln. The protein levels were normalized to STX1 (syntaxin 1) and to those of control MAPT/Tau P301S Tg neurons in the absence of Gln, respectively. CHX: cycloheximide. (C-D) Representative blots (C) and quantitative analysis (D) of monomeric and oligomeric MAPT/tau levels revealed by a non-reducing gel in DIV12-14 MAPT/Tau P301S Tg neurons incubated 24 h with CHX, CHX and Gln, or CHX, Gln, and LIs (20 µm pepstatin a and 20 µm E-64d). The protein levels were normalized to those of MAPT/Tau P301S Tg neurons with CHX alone. LIs: lysosomal inhibitors. (E and F) Representative images (E) and quantitative analysis (F) of autophagic flux in the axons of DIV10-12 MAPT/Tau P301S Tg neurons in the presence and absence of LIs (20 µm pepstatin a and 20 µm E-64d), Gln, or Gln and LIs for 24 h. The data were quantified and expressed as the number of GFP-LC3-marked AVs per 100 µm axonal length in MAPT/Tau P301S neurons. AV: autophagosome/autophagic vacuole. (G and H) Representative images (G) and quantitative analysis (H) of AV density in DIV10-12 Gln-supplemented MAPT/Tau P301S axons expressing ATG5 or ATG5 K130R in the presence and absence of 100 nM bafilomycin A 1 . Baf-A1: bafilomycin A 1 . (I-J) Representative dual-channel kymographs (I) and quantitative analysis (J) of AV motility in the axons of MAPT/Tau P301S neurons with 24 h Gln treatment. (K and L) Representative images (K) and quantitative analysis (L) of AV density in the axons of DIV10-12 control and 10 mM Gln-supplemented MAPT/Tau P301S neurons with and without 1 µm oligomycin or 100 nM antimycin A. Omy: oligomycin; AA: antimycin A. Data were quantified from five independent repeats (B and D) or were collected from the total number of neurons (n) as indicated in parentheses (F, H, J, and L) from three independent experiments. Data were expressed as the mean ± SEM and analyzed by mann-whitney U test (B), Kruskal-Wallis test with Dun’s multiple comparison post hoc test (D), or one-way ANOVA with Bonferroni’s correction (F, H, and L). Scale bars: 10 µm.

Article Snippet: MAPT/Tau P301L (rTg4510) and MAPT/Tau P301S (PS19) mouse lines [ , ] were purchased from the Jackson Laboratory.

Techniques: Control, Incubation, Expressing, MANN-WHITNEY, Comparison

OXPHOS-stimulated autophagy is mediated by mitochondrial phosphatidylethanolamine (PE) biosynthesis in tauopathy neurons. (A and B) Representative blots (A) and quantitative analysis (B) of autophagy and MAPT/tau protein levels in DIV12-14 MAPT/Tau P301S Tg neurons treated for 6 h with 10 µg/ml CHX, CHX and 10 mM Gln, or CHX, 10 mM Gln, and 0.1 mM hydroxylamine. The protein levels were normalized to the loading control USO1 and to those of control MAPT/Tau P301S neurons with CHX alone, respectively. Data were quantified from five independent repeats. HA: hydroxylamine; USO1: a Golgi marker. (C-D) Representative images (C) and quantitative analysis (D) of autophagic flux in the axons of DIV10-12 MAPT/Tau P301S neurons treated with 0.1 mM hydroxylamine for 6 h or 5 µm meclizine for 24 h in the presence or absence of 10 mM Gln. The data were quantified and expressed as the number of GFP-LC3-labeled AVs per 100 µm axonal length in MAPT/Tau P301S neurons. (E) Assessment of mitochondrial PE metabolism and biosynthesis for AV formation using NBD-phosphatidylserine (PS). PISD: phosphatidylserine decarboxylase, OMM: outer mitochondrial membrane, IMM: inner mitochondrial membrane. (F and G) Representative images (F) and quantitative analysis (G) of PE metabolism in mitochondria in the axons of DIV10-12 non-Tg neurons and MAPT/Tau P301S Tg neurons 2.5 h following the loading of NBD-PS in the presence and absence of Gln. The data were quantified and expressed as mitochondrial NBD-PE fluorescence that was normalized to non-mitochondrial NBD background signal from the same axons of non-Tg and MAPT/Tau P301S Tg neurons at time 0 and 2.5 h, respectively. (H and I) nbd-labeling of AVs in the axons of DIV10-12 MAPT/Tau P301S neurons 3 h after NBD-PS loading with and without 3 h Gln preincubation. The data were quantified and expressed as the percentage of mRFP-LC3-indicated AVs positive for the NBD fluorescence in the axons of MAPT/Tau P301S neurons with and without Gln, respectively. Arrows: NBD-positive AVs; arrowheads: NBD-negative AVs. (J) Time-lapse imaging analysis of MDAV dynamics in MAPT/Tau P301S axons administered with Gln. Asterisks: DsRed-mito-labeled mitochondria; arrows: MDAVs; arrowheads: a GFP-LC3-marked AV passing by the axon. MDAV: mitochondria-derived AV. Imaging data were quantified from the total number of neurons (n) as indicated in parentheses (D, G, and I) from more than three independent experiments. Data were expressed as the mean ± SEM and analyzed by Kruskal-Wallis test with Dun’s multiple comparison post hoc test (B), one-way ANOVA with Bonferroni’s correction (D and G), or two-sided unpaired Student’s t -test (I). Scale bars: 10 µm.

Journal: Autophagy

Article Title: Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons

doi: 10.1080/15548627.2024.2392408

Figure Lengend Snippet: OXPHOS-stimulated autophagy is mediated by mitochondrial phosphatidylethanolamine (PE) biosynthesis in tauopathy neurons. (A and B) Representative blots (A) and quantitative analysis (B) of autophagy and MAPT/tau protein levels in DIV12-14 MAPT/Tau P301S Tg neurons treated for 6 h with 10 µg/ml CHX, CHX and 10 mM Gln, or CHX, 10 mM Gln, and 0.1 mM hydroxylamine. The protein levels were normalized to the loading control USO1 and to those of control MAPT/Tau P301S neurons with CHX alone, respectively. Data were quantified from five independent repeats. HA: hydroxylamine; USO1: a Golgi marker. (C-D) Representative images (C) and quantitative analysis (D) of autophagic flux in the axons of DIV10-12 MAPT/Tau P301S neurons treated with 0.1 mM hydroxylamine for 6 h or 5 µm meclizine for 24 h in the presence or absence of 10 mM Gln. The data were quantified and expressed as the number of GFP-LC3-labeled AVs per 100 µm axonal length in MAPT/Tau P301S neurons. (E) Assessment of mitochondrial PE metabolism and biosynthesis for AV formation using NBD-phosphatidylserine (PS). PISD: phosphatidylserine decarboxylase, OMM: outer mitochondrial membrane, IMM: inner mitochondrial membrane. (F and G) Representative images (F) and quantitative analysis (G) of PE metabolism in mitochondria in the axons of DIV10-12 non-Tg neurons and MAPT/Tau P301S Tg neurons 2.5 h following the loading of NBD-PS in the presence and absence of Gln. The data were quantified and expressed as mitochondrial NBD-PE fluorescence that was normalized to non-mitochondrial NBD background signal from the same axons of non-Tg and MAPT/Tau P301S Tg neurons at time 0 and 2.5 h, respectively. (H and I) nbd-labeling of AVs in the axons of DIV10-12 MAPT/Tau P301S neurons 3 h after NBD-PS loading with and without 3 h Gln preincubation. The data were quantified and expressed as the percentage of mRFP-LC3-indicated AVs positive for the NBD fluorescence in the axons of MAPT/Tau P301S neurons with and without Gln, respectively. Arrows: NBD-positive AVs; arrowheads: NBD-negative AVs. (J) Time-lapse imaging analysis of MDAV dynamics in MAPT/Tau P301S axons administered with Gln. Asterisks: DsRed-mito-labeled mitochondria; arrows: MDAVs; arrowheads: a GFP-LC3-marked AV passing by the axon. MDAV: mitochondria-derived AV. Imaging data were quantified from the total number of neurons (n) as indicated in parentheses (D, G, and I) from more than three independent experiments. Data were expressed as the mean ± SEM and analyzed by Kruskal-Wallis test with Dun’s multiple comparison post hoc test (B), one-way ANOVA with Bonferroni’s correction (D and G), or two-sided unpaired Student’s t -test (I). Scale bars: 10 µm.

Article Snippet: MAPT/Tau P301L (rTg4510) and MAPT/Tau P301S (PS19) mouse lines [ , ] were purchased from the Jackson Laboratory.

Techniques: Control, Marker, Labeling, Membrane, Fluorescence, Imaging, Derivative Assay, Comparison

Gln supplementation-stimulated anaplerosis elevates OXPHOS activity and enhances PE biosynthesis in tauopathy mouse brain mitochondria. (A) Seahorse mitochondrial stress assay for OCR measurements of freshly isolated cortical mitochondria from the brains of non-Tg and MAPT/Tau P301S Tg mice at 6 months of age with and without 12-week Gn supplementation. Basal, maximal, and ATP production-linked respiration rates of mitochondria purified from Gln-administered non-Tg and MAPT/Tau P301S Tg mouse brains were normalized to those from control mice fed with Gln-free water, respectively. OCR, oxygen consumption rate. (B) Lipidomics analysis of the fold change of total mitochondrial PE species in the brains of 6 months of age non-Tg and MAPT/Tau P301S Tg mice administered with water or 12-week Gln. The changes of mitochondrial PE in the brains of MAPT/Tau P301S Tg control mice and non-Tg and MAPT/Tau P301S Tg mice supplemented with Gln were normalized to that of non-Tg control mouse brains fed with water, respectively. (C) Heat map analysis for molecular phospholipid species of PE extracted from 6-month-old non-Tg and MAPT/Tau P301S Tg mouse brain mitochondria with and without Gln administration. Rows represent the mean values for PEs and columns represent those of non-Tg or MAPT/Tau P301S Tg mice. (D) Relative abundance (mol%) of individual PE species in the total PE class of mitochondria in the brains of non-Tg and MAPT/Tau P301S Tg mice administered with water or Gln. Data were quantified from five animals (A) and three to four animals (B-D) in each group, respectively. Data were expressed as the mean ± SEM and analyzed by Kruskal-Wallis test with Bonferroni’s correction (A) or one-way ANOVA with Bonferroni’s correction (B and D).

Journal: Autophagy

Article Title: Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons

doi: 10.1080/15548627.2024.2392408

Figure Lengend Snippet: Gln supplementation-stimulated anaplerosis elevates OXPHOS activity and enhances PE biosynthesis in tauopathy mouse brain mitochondria. (A) Seahorse mitochondrial stress assay for OCR measurements of freshly isolated cortical mitochondria from the brains of non-Tg and MAPT/Tau P301S Tg mice at 6 months of age with and without 12-week Gn supplementation. Basal, maximal, and ATP production-linked respiration rates of mitochondria purified from Gln-administered non-Tg and MAPT/Tau P301S Tg mouse brains were normalized to those from control mice fed with Gln-free water, respectively. OCR, oxygen consumption rate. (B) Lipidomics analysis of the fold change of total mitochondrial PE species in the brains of 6 months of age non-Tg and MAPT/Tau P301S Tg mice administered with water or 12-week Gln. The changes of mitochondrial PE in the brains of MAPT/Tau P301S Tg control mice and non-Tg and MAPT/Tau P301S Tg mice supplemented with Gln were normalized to that of non-Tg control mouse brains fed with water, respectively. (C) Heat map analysis for molecular phospholipid species of PE extracted from 6-month-old non-Tg and MAPT/Tau P301S Tg mouse brain mitochondria with and without Gln administration. Rows represent the mean values for PEs and columns represent those of non-Tg or MAPT/Tau P301S Tg mice. (D) Relative abundance (mol%) of individual PE species in the total PE class of mitochondria in the brains of non-Tg and MAPT/Tau P301S Tg mice administered with water or Gln. Data were quantified from five animals (A) and three to four animals (B-D) in each group, respectively. Data were expressed as the mean ± SEM and analyzed by Kruskal-Wallis test with Bonferroni’s correction (A) or one-way ANOVA with Bonferroni’s correction (B and D).

Article Snippet: MAPT/Tau P301L (rTg4510) and MAPT/Tau P301S (PS19) mouse lines [ , ] were purchased from the Jackson Laboratory.

Techniques: Activity Assay, Isolation, Purification, Control

Anaplerotic enhancement of OXPHOS boosts autophagy and reduces MAPT/tau accumulation in tauopathy mouse brains. (A and B) Representative images (A) and quantitative analysis (B) of AV clusters (arrows) in the hippocampal regions of 9-month-old non-Tg and MAPT/Tau P301S Tg mouse brains with and without Gln supplementation. Data were quantified and normalized to those of control non-Tg and MAPT/Tau P301S Tg mouse brains fed with Gln-free water from a total number of imaging slice sections as indicated in parentheses (B) from three pairs of non-Tg and MAPT/Tau P301S Tg mice. s.p.: stratum pyramidale; mf: mossy fibers. (C and D) Representative TEM images (C) and quantitative analysis (D) of double-membrane initial AV-like structures on or near mitochondria at the presynaptic terminals of control and Gln-treated 6-month-old MAPT/Tau P301S Tg mouse brains. M: mitochondrion; arrows: AVs. Data were quantified from the total number of presynaptic terminals (n) as indicated in parentheses (D) from two pairs of MAPT/Tau P301S Tg mice. (E-G) represent blots (E) and quantitative analysis (F and G) of autophagy and MAPT/tau protein levels in detergent-extracted brain lysates from 9-month-old non-Tg and MAPT/Tau P301S Tg mice with and without Gln administration. The protein levels in the brains of non-Tg and MAPT/Tau P301S Tg mice with Gln supplementation were normalized to USO1 and to those in control mice fed with water, respectively (F and G). Data were quantified from five pairs of non-Tg and MAPT/Tau P301S Tg mice. m: murine; h: human. Data were expressed as the mean ± SEM and analyzed with mann-whitney U test (B, F, and G) or two-sided unpaired Student’s t -test (D). Scale bars: 10 µm (A) and 200 nm (C).

Journal: Autophagy

Article Title: Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons

doi: 10.1080/15548627.2024.2392408

Figure Lengend Snippet: Anaplerotic enhancement of OXPHOS boosts autophagy and reduces MAPT/tau accumulation in tauopathy mouse brains. (A and B) Representative images (A) and quantitative analysis (B) of AV clusters (arrows) in the hippocampal regions of 9-month-old non-Tg and MAPT/Tau P301S Tg mouse brains with and without Gln supplementation. Data were quantified and normalized to those of control non-Tg and MAPT/Tau P301S Tg mouse brains fed with Gln-free water from a total number of imaging slice sections as indicated in parentheses (B) from three pairs of non-Tg and MAPT/Tau P301S Tg mice. s.p.: stratum pyramidale; mf: mossy fibers. (C and D) Representative TEM images (C) and quantitative analysis (D) of double-membrane initial AV-like structures on or near mitochondria at the presynaptic terminals of control and Gln-treated 6-month-old MAPT/Tau P301S Tg mouse brains. M: mitochondrion; arrows: AVs. Data were quantified from the total number of presynaptic terminals (n) as indicated in parentheses (D) from two pairs of MAPT/Tau P301S Tg mice. (E-G) represent blots (E) and quantitative analysis (F and G) of autophagy and MAPT/tau protein levels in detergent-extracted brain lysates from 9-month-old non-Tg and MAPT/Tau P301S Tg mice with and without Gln administration. The protein levels in the brains of non-Tg and MAPT/Tau P301S Tg mice with Gln supplementation were normalized to USO1 and to those in control mice fed with water, respectively (F and G). Data were quantified from five pairs of non-Tg and MAPT/Tau P301S Tg mice. m: murine; h: human. Data were expressed as the mean ± SEM and analyzed with mann-whitney U test (B, F, and G) or two-sided unpaired Student’s t -test (D). Scale bars: 10 µm (A) and 200 nm (C).

Article Snippet: MAPT/Tau P301L (rTg4510) and MAPT/Tau P301S (PS19) mouse lines [ , ] were purchased from the Jackson Laboratory.

Techniques: Control, Imaging, Membrane, MANN-WHITNEY

Attenuation of MAPT/tau pathology in bioenergetically enhanced tauopathy mouse brains. (A and B) Representative blots (A) and quantitative analysis (B) of monomeric and oligomeric MAPT/tau levels revealed by the non-reducing gel in 9-month-old non-Tg and MAPT/Tau P301S Tg mouse brains with and without Gln treatment. Data were normalized to those of control mouse brains in the absence of Gln and quantified from five independent repeats with five mice in each group. m: murine; h: human. (C-F) Representative images (C and E) and quantitative analysis (D and F) of MAPT/tau accumulation/aggregation in the hippocampus of 9-month-old MAPT/Tau P301S Tg mouse brains with and without Gln supplementation ( n = 7-11 mouse brain slice sections in each group from two pairs of MAPT/Tau P301S Tg mice). The mean intensities of p-mapt (AT8) and p-mapt (PHF1) antibody-marked phospho-MAPT/tau in the hippocampal CA3 and CA1 areas of MAPT/Tau P301S mouse brains were quantified and normalized to those of control MAPT/Tau P301S mouse brains fed with regular water, respectively. Data were expressed as the mean ± SEM and analyzed with mann-whitney U test (B, D, and F). Scale bars: 10 µm.

Journal: Autophagy

Article Title: Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons

doi: 10.1080/15548627.2024.2392408

Figure Lengend Snippet: Attenuation of MAPT/tau pathology in bioenergetically enhanced tauopathy mouse brains. (A and B) Representative blots (A) and quantitative analysis (B) of monomeric and oligomeric MAPT/tau levels revealed by the non-reducing gel in 9-month-old non-Tg and MAPT/Tau P301S Tg mouse brains with and without Gln treatment. Data were normalized to those of control mouse brains in the absence of Gln and quantified from five independent repeats with five mice in each group. m: murine; h: human. (C-F) Representative images (C and E) and quantitative analysis (D and F) of MAPT/tau accumulation/aggregation in the hippocampus of 9-month-old MAPT/Tau P301S Tg mouse brains with and without Gln supplementation ( n = 7-11 mouse brain slice sections in each group from two pairs of MAPT/Tau P301S Tg mice). The mean intensities of p-mapt (AT8) and p-mapt (PHF1) antibody-marked phospho-MAPT/tau in the hippocampal CA3 and CA1 areas of MAPT/Tau P301S mouse brains were quantified and normalized to those of control MAPT/Tau P301S mouse brains fed with regular water, respectively. Data were expressed as the mean ± SEM and analyzed with mann-whitney U test (B, D, and F). Scale bars: 10 µm.

Article Snippet: MAPT/Tau P301L (rTg4510) and MAPT/Tau P301S (PS19) mouse lines [ , ] were purchased from the Jackson Laboratory.

Techniques: Control, Slice Preparation, MANN-WHITNEY

Early OXPHOS enhancement alleviates synapse loss and mitigates neuronal death in tauopathy mouse brains. (A and B) Representative images (A) and quantitative analysis (B) of presynaptic terminal densities in the hippocampal mossy fibers of 9-month-old non-Tg and MAPT/Tau P301S Tg mice administered with water or Gln. The area and the mean intensity of SYP-marked presynaptic terminals were quantified and normalized to non-Tg control mice with no Gln treatment, respectively. (C and D) Representative images (C) and quantitative analysis (D) of neuron density in the hippocampal regions of non-Tg and MAPT/Tau P301S Tg mouse brains with and without Gln administration. The number of RBFOX3-labeled neurons in hippocampal CA3 areas marked by rectangles was quantified and normalized to that of non-Tg mice in the absence of Gln. Data were quantified from a total number of imaging slice sections as indicated in parentheses (B and D) from three mice per group. Data were expressed as the mean ± SEM and analyzed by one-way ANOVA with Bonferroni’s correction (B and D). Scale bars: 25 µm (A and the bottom panel in C) and 250 µm (the top panel in C).

Journal: Autophagy

Article Title: Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons

doi: 10.1080/15548627.2024.2392408

Figure Lengend Snippet: Early OXPHOS enhancement alleviates synapse loss and mitigates neuronal death in tauopathy mouse brains. (A and B) Representative images (A) and quantitative analysis (B) of presynaptic terminal densities in the hippocampal mossy fibers of 9-month-old non-Tg and MAPT/Tau P301S Tg mice administered with water or Gln. The area and the mean intensity of SYP-marked presynaptic terminals were quantified and normalized to non-Tg control mice with no Gln treatment, respectively. (C and D) Representative images (C) and quantitative analysis (D) of neuron density in the hippocampal regions of non-Tg and MAPT/Tau P301S Tg mouse brains with and without Gln administration. The number of RBFOX3-labeled neurons in hippocampal CA3 areas marked by rectangles was quantified and normalized to that of non-Tg mice in the absence of Gln. Data were quantified from a total number of imaging slice sections as indicated in parentheses (B and D) from three mice per group. Data were expressed as the mean ± SEM and analyzed by one-way ANOVA with Bonferroni’s correction (B and D). Scale bars: 25 µm (A and the bottom panel in C) and 250 µm (the top panel in C).

Article Snippet: MAPT/Tau P301L (rTg4510) and MAPT/Tau P301S (PS19) mouse lines [ , ] were purchased from the Jackson Laboratory.

Techniques: Control, Labeling, Imaging

Early stimulation of mitochondrial bioenergetics leads to improvement of behavioral performance in tauopathy mice. (A) Sociability and social recognition memory assay performed in 8-month-old non-Tg and MAPT/Tau P301S Tg male mice administered with regular Gln-free water or Gln ( n = 7-11 male mice per group). n.s.: non-significant. (B-D) Morris water maze test of 8-month-old MAPT/Tau P301S Tg male mice and non-Tg littermates with and without Gln administration ( n = 7-12 male mice per group). (E) Contextual fear conditioning task performed in 8-month-old non-Tg and MAPT/Tau P301S Tg male mice supplemented with regular water or Gln ( n = 7-10 male mice per group). (F) Schematic illustration of anaplerotic stimulation of OXPHOS to power mitochondrial biosynthesis and supply of PE for AV biogenesis which enhances pathological MAPT/tau clearance in tauopathy neurons. Therefore, autophagy dysfunction and MAPT/tau accumulation can be attributed to mitochondrial bioenergetic deficiency in tauopathy. Data were shown as the mean ± SEM and analyzed with mann-whitney U test (A) or kruskal-wallis one-way analysis of variance test with Bonferroni’s correction (B-E).

Journal: Autophagy

Article Title: Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons

doi: 10.1080/15548627.2024.2392408

Figure Lengend Snippet: Early stimulation of mitochondrial bioenergetics leads to improvement of behavioral performance in tauopathy mice. (A) Sociability and social recognition memory assay performed in 8-month-old non-Tg and MAPT/Tau P301S Tg male mice administered with regular Gln-free water or Gln ( n = 7-11 male mice per group). n.s.: non-significant. (B-D) Morris water maze test of 8-month-old MAPT/Tau P301S Tg male mice and non-Tg littermates with and without Gln administration ( n = 7-12 male mice per group). (E) Contextual fear conditioning task performed in 8-month-old non-Tg and MAPT/Tau P301S Tg male mice supplemented with regular water or Gln ( n = 7-10 male mice per group). (F) Schematic illustration of anaplerotic stimulation of OXPHOS to power mitochondrial biosynthesis and supply of PE for AV biogenesis which enhances pathological MAPT/tau clearance in tauopathy neurons. Therefore, autophagy dysfunction and MAPT/tau accumulation can be attributed to mitochondrial bioenergetic deficiency in tauopathy. Data were shown as the mean ± SEM and analyzed with mann-whitney U test (A) or kruskal-wallis one-way analysis of variance test with Bonferroni’s correction (B-E).

Article Snippet: MAPT/Tau P301L (rTg4510) and MAPT/Tau P301S (PS19) mouse lines [ , ] were purchased from the Jackson Laboratory.

Techniques: MANN-WHITNEY

( A ) Schematic diagram of the experimental procedure. p.o., per os. ( B ) Composition of Amino LP7. ( C to E ) Representative coronal MR images (C), time course of cortex volume alterations (Δcortex volume) (D), and summary of Δcortex volume at 6.5 months (E) of mice in six conditions: rTg4510 mice or their littermate controls under NPD or LPD with or without Amino LP7 administration ( n = 3 to 8 for each condition). Analysis of variance (ANOVA) [ F (5,28) = 16.98, P < 0.0001] with Tukey’s post hoc test was used. ( F ) Representative cortical spine images (left) and mean spine density (right) of control, rTg4510, and rTg4510 mice with Amino LP7 administration ( n = 6 dendrites from three animals for each condition). Scale bars, 5 μm. ANOVA [ F (2,25) = 9.19, P = 0.001] with Tukey’s post hoc test was used. All data are expressed as the means ± SEM. Points represent individual animals. The difference between the means is not statistically significant ( P ≥ 0.05) for all groups with the same alphabetical symbols and is statistically significant ( P < 0.05) for two groups with different symbols. Non-Tg, littermate control; Tg, rTg4510.

Journal: Science Advances

Article Title: Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model

doi: 10.1126/sciadv.abd5046

Figure Lengend Snippet: ( A ) Schematic diagram of the experimental procedure. p.o., per os. ( B ) Composition of Amino LP7. ( C to E ) Representative coronal MR images (C), time course of cortex volume alterations (Δcortex volume) (D), and summary of Δcortex volume at 6.5 months (E) of mice in six conditions: rTg4510 mice or their littermate controls under NPD or LPD with or without Amino LP7 administration ( n = 3 to 8 for each condition). Analysis of variance (ANOVA) [ F (5,28) = 16.98, P < 0.0001] with Tukey’s post hoc test was used. ( F ) Representative cortical spine images (left) and mean spine density (right) of control, rTg4510, and rTg4510 mice with Amino LP7 administration ( n = 6 dendrites from three animals for each condition). Scale bars, 5 μm. ANOVA [ F (2,25) = 9.19, P = 0.001] with Tukey’s post hoc test was used. All data are expressed as the means ± SEM. Points represent individual animals. The difference between the means is not statistically significant ( P ≥ 0.05) for all groups with the same alphabetical symbols and is statistically significant ( P < 0.05) for two groups with different symbols. Non-Tg, littermate control; Tg, rTg4510.

Article Snippet: The rTg4510 mouse line overexpressing human 4R0N tau with the P301L mutation was licensed from Mayo Clinic, bred, and maintained at Taconic, Hudson, NY.

Techniques: Control

( A ) Heatmap illustrating the relative expression of 7086 DEGs extracted from pairwise comparisons (non-Tg + NPD versus non-Tg + LPD; non-Tg + NPD versus Tg + NPD; Tg + NPD versus Tg + NPD + Amino LP7; Tg + NPD versus Tg + LPD; Tg + LPD versus Tg + LPD + Amino LP7). The vertical and horizontal axes indicate individual animals and DEGs, respectively. ( B ) Summary of GO enrichment analysis. GO terms enriched in down- or up-regulated DEGs were ranked according to q value, and the top 10 terms in each pairwise comparison were extracted. A circle indicates significant enrichment ( q value < 0.05) of the GO term in the comparison, while its color and intensity indicate the direction (up/down) and q value of enrichment, respectively. GO terms are ordered and grouped according to automatically detected communities based on the similarity of comprising genes. ( C ) Heatmap illustrating the relative expression of representative genes in five categories. Vertical and horizontal axes indicate group mean and genes, respectively. The top 10 DEGs at the probe level contributing to significantly enriched GO terms in each pairwise comparison for each category were extracted and integrated. To improve visibility, probes indicating the same gene were summarized by the mean. Non-Tg, littermate control; Tg, rTg4510; pos., positive; neg., negative; reg., regulation; dev., development; path., pathway.

Journal: Science Advances

Article Title: Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model

doi: 10.1126/sciadv.abd5046

Figure Lengend Snippet: ( A ) Heatmap illustrating the relative expression of 7086 DEGs extracted from pairwise comparisons (non-Tg + NPD versus non-Tg + LPD; non-Tg + NPD versus Tg + NPD; Tg + NPD versus Tg + NPD + Amino LP7; Tg + NPD versus Tg + LPD; Tg + LPD versus Tg + LPD + Amino LP7). The vertical and horizontal axes indicate individual animals and DEGs, respectively. ( B ) Summary of GO enrichment analysis. GO terms enriched in down- or up-regulated DEGs were ranked according to q value, and the top 10 terms in each pairwise comparison were extracted. A circle indicates significant enrichment ( q value < 0.05) of the GO term in the comparison, while its color and intensity indicate the direction (up/down) and q value of enrichment, respectively. GO terms are ordered and grouped according to automatically detected communities based on the similarity of comprising genes. ( C ) Heatmap illustrating the relative expression of representative genes in five categories. Vertical and horizontal axes indicate group mean and genes, respectively. The top 10 DEGs at the probe level contributing to significantly enriched GO terms in each pairwise comparison for each category were extracted and integrated. To improve visibility, probes indicating the same gene were summarized by the mean. Non-Tg, littermate control; Tg, rTg4510; pos., positive; neg., negative; reg., regulation; dev., development; path., pathway.

Article Snippet: The rTg4510 mouse line overexpressing human 4R0N tau with the P301L mutation was licensed from Mayo Clinic, bred, and maintained at Taconic, Hudson, NY.

Techniques: Expressing, Comparison, Control

( A and B ) Brain (A) and plasma (B) kynurenine concentrations ( n = 3 to 9 for each condition). ANOVA [brain, F (5,28) = 7.32, P = 0.0002; plasma, F (5,27) = 2.66, P = 0.04] with Tukey’s post hoc test was used. ( C ) Schematic diagram of acute intraperitoneal injection of l -kynurenine with or without Amino LP7 in aged C57BL/6J mice under NPD or LPD. ( D and E ) Brain kynurenine (D) and QA (E) concentrations after acute l -kynurenine injections with or without Amino LP7 ( n = 9 to 11 for each condition). ANOVA [kynurenine, F (5,56) = 82.14, P < 0.0001; QA, F (5,53) = 37.73, P < 0.0001] with Tukey’s post hoc test was used. All data are expressed as the means ± SEM. Points represent individual animals. The difference between the means is not statistically significant ( P ≥ 0.05) for all groups with the same alphabetical symbols and is statistically significant ( P < 0.05) for two groups with different symbols. Non-Tg, littermate control; Tg, rTg4510; Kyn, kynurenine.

Journal: Science Advances

Article Title: Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model

doi: 10.1126/sciadv.abd5046

Figure Lengend Snippet: ( A and B ) Brain (A) and plasma (B) kynurenine concentrations ( n = 3 to 9 for each condition). ANOVA [brain, F (5,28) = 7.32, P = 0.0002; plasma, F (5,27) = 2.66, P = 0.04] with Tukey’s post hoc test was used. ( C ) Schematic diagram of acute intraperitoneal injection of l -kynurenine with or without Amino LP7 in aged C57BL/6J mice under NPD or LPD. ( D and E ) Brain kynurenine (D) and QA (E) concentrations after acute l -kynurenine injections with or without Amino LP7 ( n = 9 to 11 for each condition). ANOVA [kynurenine, F (5,56) = 82.14, P < 0.0001; QA, F (5,53) = 37.73, P < 0.0001] with Tukey’s post hoc test was used. All data are expressed as the means ± SEM. Points represent individual animals. The difference between the means is not statistically significant ( P ≥ 0.05) for all groups with the same alphabetical symbols and is statistically significant ( P < 0.05) for two groups with different symbols. Non-Tg, littermate control; Tg, rTg4510; Kyn, kynurenine.

Article Snippet: The rTg4510 mouse line overexpressing human 4R0N tau with the P301L mutation was licensed from Mayo Clinic, bred, and maintained at Taconic, Hudson, NY.

Techniques: Clinical Proteomics, Injection, Control

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