Loss of amyloid precursor protein in a mouse model of Niemann–Pick type C disease exacerbates its phenotype and disrupts tau homeostasis

Bidirectional links between Alzheimer's disease and Niemann–Pick type C disease

“…The APPsw/APP-V717F/NPC1−/− bigenic mice exhibited decreased life span, early object memory and motor impairments, exacerbated glial and astrocyte pathology, significant demyelination and accelerated neurodegeneration in the cerebellum (Maulik et al, 2012). Interestingly, while APPko mice did not show any cholesterol storage abnormalities, the loss of APP in NPC1−/− mice resulted in further cholesterol accumulation throughout the cerebellar cortex, motor cortex and hippocampus (particularly in the dentate gyrus) (Nunes et al, 2011). There was an increase in the number of vesicles accumulating cholesterol in APPko/NPC1−/− mice than in NPC1−/− mice, indicating that cholesterol homeostasis is further disrupted and upregulated upon the removal of APP.…”

“…Mice lacking both APP and NPC1 protein (APPko/NPC1−/−) as well as mice overexpressing human mutant APP (APPsw/APP-V717F) under the NPC1-null background both showed exacerbated NPC phenotype at multiple levels (Maulik et al, 2012;Nunes et al, 2011). Double APPko/NPC1−/− mice displayed shorter cumulative survival, lower birth weight and poorer motor coordination than NPC1−/− mice (Nunes et al, 2011).…”

“…Double APPko/NPC1−/− mice displayed shorter cumulative survival, lower birth weight and poorer motor coordination than NPC1−/− mice (Nunes et al, 2011). The APPsw/APP-V717F/NPC1−/− bigenic mice exhibited decreased life span, early object memory and motor impairments, exacerbated glial and astrocyte pathology, significant demyelination and accelerated neurodegeneration in the cerebellum (Maulik et al, 2012).…”

“…Therefore, both Aβ peptides and tau protein may play crucial roles in the development of Alzheimer's disease. The interrelationship between Aβ and tau pathologies in NPC disease has been revealed by crossing the APP and NPC1−/− mice (Maulik et al, 2012;Nunes et al, 2011). Strikingly, the loss of APP in NPC1−/− mice led to a substantial increase in tau abnormalities, in both cortex and cerebellum, including further reduction in tau levels and an increase of hyperphosphorylated tau (Nunes et al, 2011).…”

“…The interrelationship between Aβ and tau pathologies in NPC disease has been revealed by crossing the APP and NPC1−/− mice (Maulik et al, 2012;Nunes et al, 2011). Strikingly, the loss of APP in NPC1−/− mice led to a substantial increase in tau abnormalities, in both cortex and cerebellum, including further reduction in tau levels and an increase of hyperphosphorylated tau (Nunes et al, 2011). A similar deterioration of tau function as in APPko/NPC1−/− mice, was observed in bigenic APPsw/APP-V717F/NPC1−/− mice (Maulik et al, 2012), supporting that APP may affect tau homeostasis independently of Aβ generation.…”