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Abstract
Objective: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by intracellular accumulation of lipids such as cholesterol and glycosphingolipids in endosomes and lysosomes. This accumulation induces progressive degeneration of the nervous system. NPC shows some intriguing similarities with Alzheimer disease (AD), including neurofibrillary tangles, but patients with NPC generally lack amyloid-β (Aβ) plaques. Lipids affect γ-secretase-dependent amyloid precursor protein (APP) metabolism that generates Aβ in vitro, but this has been difficult to prove in vivo. Our aim was to assess the effect of altered lipid constituents in neuronal membranes on amyloidogenic APP processing in humans.
Methods: We examined Aβ in CSF from patients with NPC (n = 38) and controls (n = 14). CSF was analyzed for Aβ38, Aβ40, Aβ42, α-cleaved soluble APP, β-cleaved soluble APP, total-tau, and phospho-tau.
Results: Aβ release was markedly increased in NPC, with a shift toward the Aβ42 isoform. Levels of α- and β-cleaved soluble APP were similar in patients and controls. Patients with NPC had increased total-tau. Patients on treatment with miglustat (n = 18), a glucosylceramide synthase blocker, had lower Aβ42 and total-tau than untreated patients.
Conclusion: Increased CSF levels of Aβ38, Aβ40, and Aβ42 and unaltered levels of β-cleaved soluble APP are consistent with increased γ-secretase-dependent Aβ release in the brains of patients with NPC. These results provide the first in vivo evidence that neuronal lipid accumulation facilitates γ-secretase-dependent Aβ production in humans and may be of relevance to AD pathogenesis.
Footnotes
Study funding: Supported by the Swedish Research Council (projects 14002, 2006-6227, 2006-2740, and 2006-3505), the Alzheimer's Association (NIRG-08-90356), cNEUPRO, the Royal Swedish Academy of Sciences, Sahlgrenska University Hospital, the Söderberg Foundation, the Gothenburg Medical Society, the Swedish Medical Society, Swedish Brain Power, Stiftelsen Gamla Tjänarinnor, the Lundbeck Foundation, Gun och Bertil Stohnes stiftelse, Åhlén-stiftelsen, The Swedish Brain Fund, Alzheimer Foundation, Sweden, The Dementia Association, Sweden, a Bench to Bedside grant from the NIH Office of Rare Diseases, and the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Editorial, page 316
Supplemental data at www.neurology.org
References e1–e18 are available on the Neurology® Web site at www.neurology.org.
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- AD
- Alzheimer disease
- APP
- amyloid precursor protein
- CV
- coefficient of variation
- NICHD
- National Institute of Child Health and Development
- NPC
- Niemann-Pick disease type C
- P-tau
- phosphorylated tau
- Received June 9, 2010.
- Accepted September 9, 2010.
- Copyright © 2011 by AAN Enterprises, Inc.
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