title: Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease.
abstract: Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aβ), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipid de novo synthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic AD postmortem brains, suggesting that SPT is involved in AD pathology.
authors.affiliation: Neurodegeneration and Neurobiology, Deutsches Institut für Demenzprävention (DIDP), Kirrbergerstraße, 66421 Homburg, Germany.
authors.forename: Marcus O W
authors.initials: MO
authors.lastname: Grimm
authors.forename: Sven
authors.initials: S
authors.lastname: Grösgen
authors.forename: Tatjana L
authors.initials: TL
authors.lastname: Rothhaar
authors.forename: Verena K
authors.initials: VK
authors.lastname: Burg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hundsdörfer
authors.forename: Viola J
authors.initials: VJ
authors.lastname: Haupenthal
authors.forename: Petra
authors.initials: P
authors.lastname: Friess
authors.forename: Ulrike
authors.initials: U
authors.lastname: Müller
authors.forename: Klaus
authors.initials: K
authors.lastname: Fassbender
authors.forename: Matthias
authors.initials: M
authors.lastname: Riemenschneider
authors.forename: Heike S
authors.initials: HS
authors.lastname: Grimm
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann