Arf6 controls beta-amyloid production by regulating macropinocytosis of the
Amyloid Precursor Protein to lysosomes
#MMPMID26170135
Tang W
; Tam JH
; Seah C
; Chiu J
; Tyrer A
; Cregan SP
; Meakin SO
; Pasternak SH
Mol Brain
2015[Jul]; 8
(?): 41
PMID26170135
show ga
Alzheimer's disease (AD) is characterized by the deposition of Beta-Amyloid (A?)
peptides in the brain. A? peptides are generated by cleavage of the Amyloid
Precursor Protein (APP) by the ??-?and ??-?secretase enzymes. Although this
process is tightly linked to the internalization of cell surface APP, the
compartments responsible are not well defined. We have found that APP can be
rapidly internalized from the cell surface to lysosomes, bypassing early and late
endosomes. Here we show by confocal microscopy and electron microscopy that this
pathway is mediated by macropinocytosis. APP internalization is enhanced by
antibody binding/crosslinking of APP suggesting that APP may function as a
receptor. Furthermore, a dominant negative mutant of Arf6 blocks direct transport
of APP to lysosomes, but does not affect classical endocytosis to endosomes. Arf6
expression increases through the hippocampus with the development of Alzheimer's
disease, being expressed mostly in the CA1 and CA2 regions in normal individuals
but spreading through the CA3 and CA4 regions in individuals with pathologically
diagnosed AD. Disruption of lysosomal transport of APP reduces both A?40 and A?42
production by more than 30 %. Our findings suggest that the lysosome is an
important site for A? production and that altering APP trafficking represents a
viable strategy to reduce A? production.
|*Pinocytosis
[MESH]
|ADP-Ribosylation Factor 1/metabolism
[MESH]
|ADP-Ribosylation Factor 6
[MESH]
|ADP-Ribosylation Factors/*metabolism
[MESH]
|Actins/metabolism
[MESH]
|Alcohol Oxidoreductases/metabolism
[MESH]
|Alzheimer Disease/metabolism/pathology
[MESH]
|Amyloid beta-Peptides/*biosynthesis
[MESH]
|Animals
[MESH]
|Cell Compartmentation
[MESH]
|Cell Line, Tumor
[MESH]
|Cell Membrane/metabolism/ultrastructure
[MESH]
|Cell Survival
[MESH]
|Cross-Linking Reagents/metabolism
[MESH]
|DNA-Binding Proteins/metabolism
[MESH]
|Dextrans/metabolism
[MESH]
|Endosomes/metabolism/ultrastructure
[MESH]
|Gene Knockdown Techniques
[MESH]
|Hippocampus/metabolism
[MESH]
|Humans
[MESH]
|Lysosomal-Associated Membrane Protein 1/metabolism
[MESH]
free
free
free
