F-box only protein 2 (Fbxo2) regulates amyloid precursor protein levels and processing.
The amyloid precursor protein (APP) is an integral membrane glycoprotein whose cleavage products, particularly amyloid-β, accumulate in Alzheimer disease (AD). APP is present at synapses and is thought to play a role in both the formation and plasticity of these critical neuronal structures. Despite the central role suggested for APP in AD pathogenesis, the mechanisms regulating APP in neurons and its processing into cleavage products remain incompletely understood. F-box only protein 2 (Fbxo2), a neuron-enriched ubiquitin ligase substrate adaptor that preferentially binds high-mannose glycans on glycoproteins, was previously implicated in APP processing by facilitating the degradation of the APP-cleaving β-secretase, β-site APP-cleaving enzyme. Here, we sought to determine whether Fbxo2 plays a similar role for other glycoproteins in the amyloid processing pathway. We present in vitro and in vivo evidence that APP is itself a substrate for Fbxo2. APP levels were decreased in the presence of Fbxo2 in non-neuronal cells, and increased in both cultured hippocampal neurons and brain tissue from Fbxo2 knock-out mice. The processing of APP into its cleavage products was also increased in hippocampi and cultured hippocampal neurons lacking Fbxo2. In hippocampal slices, this increase in cleavage products was accompanied by a significant reduction in APP at the cell surface. Taken together, these results suggest that Fbxo2 regulates APP levels and processing in the brain and may play a role in modulating AD pathogenesis.
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48104. Electronic address: atking@umich.edu.
Graham
G
Atkin
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48104.
Jack
J
Hunt
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48104.
Eiko
E
Minakawa
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48104.
Lisa
L
Sharkey
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48104.
Nathan
N
Tipper
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48104.
William
W
Tennant
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48104. Electronic address: henryp@umich.edu.
Henry L
HL
Paulson
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D044783:F-Box Proteins; C500719:Fbx2 protein, mouse
Amyloid Precursor Protein; Neurobiology; Protein Targeting; Synapses; Ubiquitination