NPC1-/- Mouse Model
Defects in NPC1 cause Niemann-Pick disease type C1, an inherited lysosomal storage disorder that affects the viscera and the central nervous system. The disease is caused by defective intracellular processing and transport of low-density lipoprotein derived cholesterol and it causes accumulation of cholesterol in lysosomes, with delayed induction of cholesterol homeostatic reactions (Mattsson et al., 2012).
Interestingly, NPC disease shares similarities with Alzheimer’s disease (AD) showing progressive neurodegeneration, accumulation of amyloid-beta peptides, APP C-terminal fragments (Mattsson et al., 2012) and hyperphosphorylated tau (Ohm et al., 2003). The AD-like pathological features were identified both in the brains of NPC patients and NPC (NPC1-/-) mouse model (Mattsson et al., 2012).
Typical pathological features of Niemann-Pick disease:
- Increased cholesterol levels
- Progressive neuronal loss (especially Purkinje cells of the cerebellum)
- Altered APP expression and accumulation of amyloid-beta peptides
- Motor coordination deficits
Figure 1: Absence of NPC1 in 7 weeks old NPC1-/- animals leads to increased liver weight (left side) and decreased brain weight (right side). NPC-/- n=12, NPC+/+ n=6; Statistical analysis: Student`s ttest, **p<0.01; ***p<0.001.
Tissue Cholesterol Levels
Figure 2. Absence of NPC1 in 7 weeks old NPC1-/- animals leads to cholesterol accumulation in the liver (left panel) but not in the brain (right panel). NPC-/- n=12, NPC+/+ n=6; Statistical analysis: Student`s t-test, ***p<0.001.
Purkinje Cell Degeneration in NPC1-/- Mice
Figure 3: NPC knockout mice are among other pathological changes characterized by a fast loss of neurons in the cerebellum, including Purkinje cells. Note that especially in anterior parts of the cerebellum the calbindin IR Purkinje cell network largely breaks down. Only small stripes remain as indicated by the arrow (3). Healthy Purkinje cells are furthermore positive for APP (green, ab Y188).
Neuroinflammation in NPC1-/- Mice
Figure 4. NPC knockout mice are among other pathological changes characterized by a fast loss of neurons in the cerebellum (decreased MAP2 labeling (blue), which is accompanied by neuroinflammatory response seen as activated microglia and astrocytosis. Note the strong microgliosis especially in anterior parts of the cerebellum where the calbindin IR Purkinje cell network largely breaks down. CD45 IR activated microglia (red) is absent in wildtype mice. The size of observed microglia is enormous, indicating phagocytic and also hypertrophic microglia. These cells can be found mainly in the white matter but also in the Purkinje cell layer, an area where also an increased number of astrocytes (green) are located.
Motor Coordination Deficits Over Age
Figure 5: Assessment of motor coordination over age. Latency to fall from the rod of the RotaRod (A) and step cycle the time in gait analysis (B) of 5 and 7 weeks old mice. NPC-/- n=10, NPC+/+ n=5; Statistical analysis: Student`s ttest, **p<0.01.
We would be happy to test your compounds in the NPC1-/- mouse model!
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Mattsson N, Olsson M, Gustavsson MK, Kosicek M, Malnar M, Månsson E, Blomqvist M, Gobom J, Andreasson U, Brinkmalm G, Vite C, Hecimovic S, Hastings C, Blennow K, Zetterberg H, Portelius E. Amyloid-β metabolism in Niemann-Pick C disease models and patients. Metab Brain Dis. 2012 Dec;27(4):573-85. doi:10.1007/s11011-012-9332-8. Epub 2012 Sep 1.
Ohm TG, Treiber-Held S, Distl R, Glöckner F, Schönheit B, Tamanai M, Meske V. Cholesterol and tau protein–findings in Alzheimer’s and Niemann Pick C’s disease. Pharmacopsychiatry. 2003 Sep;36 Suppl 2:S120-6.