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 Aβ(38), Aβ(40), Aβ(42), 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 Aβ(42) 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 Aβ(42) and total-tau than untreated patients.

Conclusion: Increased CSF levels of Aβ(38), Aβ(40), and Aβ(42) 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.