Journal: Neural Regeneration Research

Article Title: Short-lived Niemann-Pick type C mice with accelerated brain aging as a novel model for Alzheimer’s disease research

doi: 10.4103/NRR.NRR-D-24-01190

Figure Lengend Snippet: Minor Feasibility assessments to characterize motor function loss and ataxia in the NPC1 mut mouse model (both sexes) before the onset of neurological impairment. (A) Mass and (B) survival of WT and NPC1mut mice. No WT animals died during the observation period of 20 weeks, and the median humane survival of NPC1 mut mice was 15 weeks (105 days). n = 9 for all groups for the survival assay. n = 22 for NPC1 mut mice and n = 14 for WT mice for the weight loss study. Data in A represent mean + SD analyzed by mixed-effects model (REML) followed by Šídák’s multiple comparisons test to account for animals that died before week 15, * P < 0.05. (C) Mice were observed daily for the appearance of visible tremors. The median age at which NPC1 mut mice develop tremors was eight weeks. (D–G) Coordination testing of NPC1 mut mice at 13 weeks of age using Rotarod testing at 15 revolutions per minute (D), and a battery of tests (E–G) developed specifically to monitor NPC1-related motor dysfunction as previously described. n = 11 for all groups. (D–G) Data represents mean ± SD and analyzed by unpaired two-tail t -test, * P < 0.05, **** P < 0.0001. NPC: Niemann-Pick type C disease; WT: wild-type.

Article Snippet: Wild-type (WT; C57BL/6) and Npc1 tm(I1061T)Dso , mice (hereafter referred to as NPC1 mut , Strain# 027704, The Jackson Laboratory, Bar Harbor, ME, USA) (Praggastis et al., 2015) were bred and housed under a protocol approved by the VCU Institutional Animal Care and Use Committee (AD10000977, approved December 14, 2022), which has received accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care.

Techniques: Clonogenic Cell Survival Assay, Battery

Journal: Neural Regeneration Research

Article Title: Short-lived Niemann-Pick type C mice with accelerated brain aging as a novel model for Alzheimer’s disease research

doi: 10.4103/NRR.NRR-D-24-01190

Figure Lengend Snippet: Sex-dependent gene expression changes in NPC1 mut mice. (A) The heatmap depicting the similarities and differences in differential expression of significantly altered genes in frontal cortex brain samples across NPC1 mut mice and age- and gender-matched WT controls. (B, C) Venn diagrams depict the commonality analysis results on DEGs from female and male NPC1 mut mice relative to age and gender-matched WT controls. (B) Among the 714 downregulated genes from female samples and 75 from the male mice, 39 genes are common. (C) Similarly, 51 genes are commonly upregulated between female and male mice samples. Additional Table 5 contains the complete list of DEGs, normalized reads, P values, and the common gene list. DEGs: Differentially expressed genes; NPC: Niemann-Pick type C disease; WT: wild-type.

Article Snippet: Wild-type (WT; C57BL/6) and Npc1 tm(I1061T)Dso , mice (hereafter referred to as NPC1 mut , Strain# 027704, The Jackson Laboratory, Bar Harbor, ME, USA) (Praggastis et al., 2015) were bred and housed under a protocol approved by the VCU Institutional Animal Care and Use Committee (AD10000977, approved December 14, 2022), which has received accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care.

Techniques: Gene Expression, Quantitative Proteomics

Journal: Neural Regeneration Research

Article Title: Short-lived Niemann-Pick type C mice with accelerated brain aging as a novel model for Alzheimer’s disease research

doi: 10.4103/NRR.NRR-D-24-01190

Figure Lengend Snippet: tAge prediction and association of gene expression changes in NPC1 mut mice with aging biomarkers. Relative transcriptomic ages (tAges) of control and NPC1 mut mouse brain samples (A) chronological and (B) biological aging. Difference between groups was estimated for each sex. Data are mean ± standard deviation of posterior prediction. Labels reflect Benjamini-Hochberg (BH) adjusted P -values. (C) Spearman correlation between normalized enrichment scores (NES) of pathways associated with NPC1mut and established signatures of aging and mortality. Signatures of aging and expected hazard are labeled in red, whereas signatures NPC1 mut mice are labeled in dark blue. (D) Functional enrichment (GSEA). Pathways enriched by gene expression changes induced in NPC1 mut mice (dark blue) from the current study as well as by established signatures of aging and mortality (red). Only functions significantly enriched by at least one signature ( P adjusted < 0.1) are presented. The whole list of enriched functions is provided in Additional file 3. NPC: Niemann-Pick type C disease.

Article Snippet: Wild-type (WT; C57BL/6) and Npc1 tm(I1061T)Dso , mice (hereafter referred to as NPC1 mut , Strain# 027704, The Jackson Laboratory, Bar Harbor, ME, USA) (Praggastis et al., 2015) were bred and housed under a protocol approved by the VCU Institutional Animal Care and Use Committee (AD10000977, approved December 14, 2022), which has received accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care.

Techniques: Gene Expression, Control, Standard Deviation, Labeling, Functional Assay

Journal: Neural Regeneration Research

Article Title: Short-lived Niemann-Pick type C mice with accelerated brain aging as a novel model for Alzheimer’s disease research

doi: 10.4103/NRR.NRR-D-24-01190

Figure Lengend Snippet: Immunohistochemical analysis of microglia and astrocytes in the Hippocampus of male and female mice of NPC1 mut mice. Confocal images of the Hippocampus from (A) female and (B) male mice in two groups: control (CTRL) and NPC1 mut mice. Astrocytes are labeled in red (GFAP), microglia in green (Iba1), and nuclei in blue (DAPI). An increase in microglial density is observed in the NPC1 group compared to the CTRL group in both genders. Quantitative comparison of microglial count (Iba1 + cells) in female (C) and male mice (D) across the two groups, showing a significant increase in microglial numbers in the NPC1 group compared to the CTRL group (two-tailed t -test; P < 0.05). DAPI: 4’,6-Diamidino-2-phenylindole; GFAP: glial fibrillary acidic protein; Iba-1: ionized calcium-binding adapter molecule 1; NPC: Niemann-Pick type C disease; WT: wild-type.

Article Snippet: Wild-type (WT; C57BL/6) and Npc1 tm(I1061T)Dso , mice (hereafter referred to as NPC1 mut , Strain# 027704, The Jackson Laboratory, Bar Harbor, ME, USA) (Praggastis et al., 2015) were bred and housed under a protocol approved by the VCU Institutional Animal Care and Use Committee (AD10000977, approved December 14, 2022), which has received accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care.

Techniques: Immunohistochemical staining, Control, Labeling, Comparison, Two Tailed Test, Binding Assay

Journal: Neural Regeneration Research

Article Title: Short-lived Niemann-Pick type C mice with accelerated brain aging as a novel model for Alzheimer’s disease research

doi: 10.4103/NRR.NRR-D-24-01190

Figure Lengend Snippet: Cross-comparison of gene expression commonalities between frontal cortex samples of NPC1 mut mice and human AD brain samples. Upset plot (A) and Venn diagram (B) depicting the downregulated genes common to AD brain samples from humans and human orthologs from the NPC1 mut mouse model. Only 6 genes; COL5A1 , DLK2 , ANKRD4 , MATK , MIAT , and MICAL2 , are downregulated in all sample types. In total, 68 downregulated genes are common to AD brain samples and NPC1 mut female mouse models. In contrast, only 6 downregulated genes were common to the AD brain and NPC1 mut male mouse samples. Upset plot (C) and Venn diagram (D) depicting the upregulated genes common to AD brain samples from humans and human orthologs from the NPC1 mut mouse model. There are 6 upregulated genes, PCDHGB3 , ABCA1 , CHD7 , FLT1 , RNF213 , and MYO10 , common to all sample types. Similarly, 6 upregulated genes are common in AD brain samples and NPC1 mut mouse male samples. In total, 119 upregulated genes are common in human AD brain and NPC1 mut mouse female samples. The complete list of the commonly altered genes can be found in Additional Table 9 . AD: Alzheimer’s disease; NPC: Niemann-Pick type C disease.

Article Snippet: Wild-type (WT; C57BL/6) and Npc1 tm(I1061T)Dso , mice (hereafter referred to as NPC1 mut , Strain# 027704, The Jackson Laboratory, Bar Harbor, ME, USA) (Praggastis et al., 2015) were bred and housed under a protocol approved by the VCU Institutional Animal Care and Use Committee (AD10000977, approved December 14, 2022), which has received accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care.

Techniques: Comparison, Gene Expression

Journal: Neural Regeneration Research

Article Title: Short-lived Niemann-Pick type C mice with accelerated brain aging as a novel model for Alzheimer’s disease research

doi: 10.4103/NRR.NRR-D-24-01190

Figure Lengend Snippet: PPI networks and pathway enrichment analysis for the common DEGs between AD human brain and NPC1 mut female and male mice brain samples. (A) PPI network and enriched pathways for the commonly up (red) and downregulated (blue) genes from . MAPK signaling, PI3K–Akt signaling, apolipoprotein binding, and Regulation of actin signaling pathways are among the enriched pathways for the upregulated genes. The thickness of the connecting lines indicates the confidence of the interactions between the connected proteins. The enrichment analyses revealed a single significantly enriched pathway associated with calmodulin-dependent protein kinase activity. (B) Significantly enriched pathways were identified with GO and KEGG pathway terms for commonly upregulated genes in AD brain samples and the human orthologs of upregulated genes from male and female NPC1 mut mice brain samples. Certain pathways, such as actin cytoskeleton regulation, apolipoprotein binding, MAPK signaling, PI3K–Akt signaling, and toxoplasmosis, are commonly enriched across different categories, reinforcing the importance of these pathways. AD: Alzheimer’s disease; DEGs: differentially expressed genes; NPC: Niemann-Pick type C disease.

Article Snippet: Wild-type (WT; C57BL/6) and Npc1 tm(I1061T)Dso , mice (hereafter referred to as NPC1 mut , Strain# 027704, The Jackson Laboratory, Bar Harbor, ME, USA) (Praggastis et al., 2015) were bred and housed under a protocol approved by the VCU Institutional Animal Care and Use Committee (AD10000977, approved December 14, 2022), which has received accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care.

Techniques: Binding Assay, Protein-Protein interactions, Activity Assay

Journal: Molecular Genetics and Metabolism Reports

Article Title: Modulation of glutamate metabolism in Niemann-pick disease type C1 mice

doi: 10.1016/j.ymgmr.2026.101303

Figure Lengend Snippet: Evaluation of perampanel treatment and Slc1a6 loss in NPC1 disease. A) Phenotypic characterization of Npc1 −/− treated with vehicle (DMSO, open red circles) or perampanel (closed red circles). Data for DMSO (green open circles) and perampanel (green closed circles) treated Npc1 +/+ mice is also provided. B) Kaplan-Meier survival curves for Npc1 −/− mice treated with vehicle (DMSO, red dashed curve, n = 13) or perampanel (green solid curve, n = 14). C) Phenotypic disease progression in Npc1 −/− :Slc1a6 +/+ (red dashed line), Npc1 −/− :Slc1a6 +/− (blue line) and Npc1 −/− :Slc1a6 −/− (green line) mice. D) Kaplan-Meier survival curves for Npc1 −/− :Slc1a6 +/+ (red dashed line, n = 12), Npc1 −/− :Slc1a6 +/− (blue line, n = 13) and Npc1 −/− :Slc1a6 −/− (green line, n = 12). E) Photomicrograph of a longitudinal cerebellar section immunostained for calbindin D (CALB, red, Purkinje neurons), glial fibrillary acidic protein (GFAP, green, astrocytes) and CD68 (yellow, microglia). F) Quantification of Purkinje neuron density in cerebellar lobules I through X. Npc1 +/+ :Slc1a6 +/+ (black); Npc1 +/+ :Slc1a6 −/− (purple); Npc1 −/− :Slc1a6 +/+ (red); Npc1 −/− :Slc1a6 −/− (green).

Article Snippet: BALB/cNctr- Npc1 m1M (strain 003092, hereafter referred to as Npc1 −/− ) mice were initially obtained from Jackson Laboratories and Slc1a6 mutant mice were generated by Applied StemCell.

Techniques: Biomarker Discovery

Journal: bioRxiv

Article Title: Unveiling Lipid Dysregulation: Lipidomics of Mouse Brain and Isolated Myelin in Niemann–Pick Disease Type C1

doi: 10.64898/2026.02.07.704575

Figure Lengend Snippet: Volcano plots for the differential LC-MS lipidomics in the NPC1 mouse cerebellum and cortex. An unpaired t-test was performed between the Npc1 −/− and Npc1 +/+ at each time point, and the Log2 Fold change (FC) was plotted against the -Log 10 p-value to generate volcano plots. A) 3 weeks cerebellum B) 7 weeks cerebellum C) 9 weeks cerebellum D) 3 weeks cortex E) 7 weeks cortex F) 9 weeks cortex. All the data points with p-value < 0.05 are highlighted in red. Dotted lines are added to intercept the x-axis at FC = 1.5 and FC = −1.5 to show the FC cut off and for the y-axis at p-value = 0.05.

Article Snippet: The Balb/c Npc1 heterozygote ( Npc1 +/− ) mice were obtained from The Jackson Laboratory (RRID:IMSR JAX:003092), and a breeding colony was maintained in our laboratory.

Techniques: Liquid Chromatography with Mass Spectroscopy

Journal: bioRxiv

Article Title: Unveiling Lipid Dysregulation: Lipidomics of Mouse Brain and Isolated Myelin in Niemann–Pick Disease Type C1

doi: 10.64898/2026.02.07.704575

Figure Lengend Snippet: Glycerophospholipids and Lyso Glycerophospholipids show statistically significant changes in the Npc1 −/− tissues. A) Cerebellum and B) Cortex differential Glycerophospholipids at each time point. C) Cerebellum and D) Cortex differential Lyso-Glycerophospholipids at each time point. Summed, normalized abundances of the differential lipids were used to calculate the Log2 Fold change (FC) and used to create the bubble plots. Bubble size is scaled to represent the percentage of significantly different lipid species compared to number of total identified lipid species in each lipid class. Unpaired t-tests were conducted between Npc1 −/− and Npc1 +/+ for each time point and each tissue to calculate the p-values and the lipid changes with a p-value < 0.05 and FC > 1.5 were considered significant. All the lipids included in the calculations show statistically significant differences between the Npc1 −/− and Npc1 +/+ groups. The three most prominent Bis(monoacylglycero)phosphate (BMP) species show severe accumulation in the Npc1 −/− E) cerebellum F) cortex tissues. G) cerebellum H) cortex Lysophosphatidylglycerol (LPG) species that show significant accumulation in the null. Peak areas normalized to internal standards were used to create the box and whisker plots.

Article Snippet: The Balb/c Npc1 heterozygote ( Npc1 +/− ) mice were obtained from The Jackson Laboratory (RRID:IMSR JAX:003092), and a breeding colony was maintained in our laboratory.

Techniques: Whisker Assay

Journal: bioRxiv

Article Title: Unveiling Lipid Dysregulation: Lipidomics of Mouse Brain and Isolated Myelin in Niemann–Pick Disease Type C1

doi: 10.64898/2026.02.07.704575

Figure Lengend Snippet: Sphingolipids show significant changes in Npc1 −/− tissues. A) cerebellum and B) cortex differential sphingolipids at each time point. Summed, normalized abundances of the differential lipids were used to calculate the Log2 Fold change (FC) and used to create the bubble plots. Bubble size is scaled to represent the percentage of the significantly different lipid species compared to number of total identified lipid species in each lipid class. An Unpaired t-test was conducted between Npc1 −/− and Npc1 +/+ for each time point and each tissue to calculate the p-values and the lipids with p-value < 0.05 and FC > 1.5 were considered significant. All the lipids included in the calculations are significantly different between the 2 groups. Ganglioside GM3 species showing severe accumulation in the Npc1 −/− C) cerebellum D) cortex tissues. Psychosine and dihexosylceramide (Hex2Cer) species that show significant accumulation in the Npc1 −/− E) Cerebellum F) Cortex tissues. Peak areas normalized to the internal standards were used to create the box and whisker plots.

Article Snippet: The Balb/c Npc1 heterozygote ( Npc1 +/− ) mice were obtained from The Jackson Laboratory (RRID:IMSR JAX:003092), and a breeding colony was maintained in our laboratory.

Techniques: Whisker Assay

Journal: bioRxiv

Article Title: Unveiling Lipid Dysregulation: Lipidomics of Mouse Brain and Isolated Myelin in Niemann–Pick Disease Type C1

doi: 10.64898/2026.02.07.704575

Figure Lengend Snippet: Decrease of cholesterol levels in the Npc1 −/− cerebellum and cortex tissues. Peak areas normalized to the internal standards were used to create the box and whisker plots. An unpaired t-test was conducted to determine the p-value. p-value > 0.05 is considered as nonsignificant (ns)

Article Snippet: The Balb/c Npc1 heterozygote ( Npc1 +/− ) mice were obtained from The Jackson Laboratory (RRID:IMSR JAX:003092), and a breeding colony was maintained in our laboratory.

Techniques: Whisker Assay

Journal: bioRxiv

Article Title: Unveiling Lipid Dysregulation: Lipidomics of Mouse Brain and Isolated Myelin in Niemann–Pick Disease Type C1

doi: 10.64898/2026.02.07.704575

Figure Lengend Snippet: Density-based myelin isolation from mice brain cerebellum and cortex A) Workflow. Isolated myelin from each genotype at age B) 5 weeks and C) 9 weeks shows decreased myelin in the Npc1 −/− . Severe dysmyelination is observed in the cortex compared to the cerebellum. Unpaired t-test was performed to determine the p-value. (p-value < 0.001, ****, p-value < 0.01, **, p-value < 0.05, *)

Article Snippet: The Balb/c Npc1 heterozygote ( Npc1 +/− ) mice were obtained from The Jackson Laboratory (RRID:IMSR JAX:003092), and a breeding colony was maintained in our laboratory.

Techniques: Isolation

Journal: bioRxiv

Article Title: Unveiling Lipid Dysregulation: Lipidomics of Mouse Brain and Isolated Myelin in Niemann–Pick Disease Type C1

doi: 10.64898/2026.02.07.704575

Figure Lengend Snippet: Differential lipids in the myelin isolated from Npc1 −/− mice cortex region at A) 5 weeks, and B) 9 weeks time points. Number of differential lipid species per lipid class is plotted in the y-axis. Number of accumulated lipid species is shown in orange color and the depleted lipids are represented by white color. Unpaired t-tests were conducted between Npc1 −/− and Npc1 +/+ for each time point and each tissue to calculate the p-values and the lipid changes with a p-value < 0.05 and FC > 1.5 were considered significant.

Article Snippet: The Balb/c Npc1 heterozygote ( Npc1 +/− ) mice were obtained from The Jackson Laboratory (RRID:IMSR JAX:003092), and a breeding colony was maintained in our laboratory.

Techniques: Isolation