title: Mutant human APP exacerbates pathology in a mouse model of NPC and its reversal by a β-cyclodextrin.
abstract: Niemann-Pick type C (NPC) disease, an autosomal recessive disorder caused primarily by loss-of-function mutations in NPC1 gene, is characterized neuropathologically by intracellular cholesterol accumulation, gliosis and neuronal loss in selected brain regions. Recent studies have shown that NPC disease exhibits intriguing parallels with Alzheimer's disease (AD), including the presence of tau-positive neurofibrillary tangles (NFTs) and β-amyloid (Aβ)-related peptides in vulnerable brain regions. Since enhanced cholesterol level, which acts as a risk factor for AD, can increase Aβ production by regulating amyloid precursor protein (APP) metabolism, it is possible that APP overexpression can influence cholesterol-regulated NPC pathology. We have addressed this issue in a novel bigenic mice (ANPC) generated by crossing heterozygous Npc1-deficient mice with mutant human APP transgenic mice. These mice exhibited decreased lifespan, early object memory and motor impairments, and exacerbated glial pathology compared with other littermates. Neurodegeneration observed in the cerebellum of ANPC mice was found to be accelerated along with a selective increase in the phosphorylation/cleavage of tau protein. Additionally, enhanced levels/activity of cytosolic cathepsin D together with cytochrome c and Bcl-2-associated X protein suggest a role for the lysosomal enzyme in the caspase-induced degeneration of neurons in ANPC mice. The reversal of cholesterol accretion by 2-hydroxypropyl-β-cyclodextrin (2-HPC) treatment increased longevity and attenuated behavioral/pathological abnormalities in ANPC mice. Collectively, our results reveal that overexpression of APP in Npc1-deficient mice can negatively influence longevity and a wide spectrum of behavioral/neuropathological abnormalities, thus raising the possibility that APP and NPC1 may interact functionally to regulate the development of AD and NPC pathologies.
authors.affiliation: Department of Medicine (Neurology), Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
authors.forename: Mahua
authors.initials: M
authors.lastname: Maulik
authors.forename: Bibaswan
authors.initials: B
authors.lastname: Ghoshal
authors.forename: John
authors.initials: J
authors.lastname: Kim
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.forename: Satyabrata
authors.initials: S
authors.lastname: Kar
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D013569:Synapses / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D047392:beta-Cyclodextrins; D016875:tau Proteins; D002784:Cholesterol; D002402:Cathepsin D