Downregulation of myosin II-B by siRNA alters the subcellular localization of the amyloid precursor protein and increases amyloid-beta deposition in N2a cells.
The Alzheimer's disease (AD) brain pathology is characterized by extracellular deposits of amyloid-beta (Abeta) peptides and intraneuronal fibrillar structures. These pathological features may be functionally linked, but the mechanism by which Abeta accumulation relates to neuronal degeneration is still poorly understood. Abeta peptides are fragments cleaved from the amyloid precursor protein (APP), a transmembrane protein ubiquitously expressed in the nervous system. Although the proteolytic processing of APP has been implicated in AD, the physiological function of APP and the subcellular site of APP cleavages remain unknown. The overall structure of the protein and its fast anterograde transport along the axon support the idea that APP functions as a vesicular receptor for cytoskeletal motor proteins. In the current study, we test the hypothesis that myosin II, important contributor to the cytoskeleton of neuronal cells, may influence the trafficking and/or the processing of APP. Our results demonstrate that downregulation of myosin II-B, the major myosin isoform in neurons, is able to increase Abeta deposition, concomitantly altering the subcellular localization of APP. These new insights might be important for the understanding of the function of APP and provide a novel conceptual framework in which to analyze its pathological role.
Massone
Sara
S
Department of Experimental Medicine, University of Genoa, Via L.B. Alberti 2, 16132 Genoa, Italy.
Argellati
Francesca
F
Passalacqua
Mario
M
Armirotti
Andrea
A
Melone
Luca
L
d'Abramo
Cristina
C
Marinari
Umberto M
UM
Domenicotti
Cinzia
C
Pronzato
Maria A
MA
Ricciarelli
Roberta
R
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D019921:Biotinylation; D002462:Cell Membrane / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D024501:Nonmuscle Myosin Type IIB / Q000096:biosynthesis* / Q000737:chemistry; D020033:Protein Isoforms; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*
D000682:Amyloid; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D024501:Nonmuscle Myosin Type IIB