Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice.
In transgenic mice expressing human mutant beta-amyloid precursor protein (APP) and mutant presenilin-1 (PS1), Abeta antibodies labeled granules, about 1 microm in diameter, in the perikaryon of neurons clustered in the isocortex, hippocampus, amygdala, thalamus, and brainstem. The granules were present before the onset of Abeta deposits; their number increased up to 9 months and decreased in 15-month-old animals. They were immunostained by antibodies against Abeta 40, Abeta 42, and APP C-terminal region. In double immunofluorescence experiments, the intracellular Abeta co-localized with lysosome markers and less frequently with MG160, a Golgi marker. Abeta accumulation correlated with an increased volume of lysosomes and Golgi apparatus, while the volume of endoplasmic reticulum and early endosomes did not change. Some granules were immunolabeled with an antibody against flotillin-1, a raft marker. At electron microscopy, Abeta, APP-C terminal, cathepsin D, and flotillin-1 epitopes were found in the lumen of multivesicular bodies. This study shows that Abeta peptide and APP C-terminal region accumulate in multivesicular bodies containing lysosomal enzymes, while APP N-terminus is excluded from them. Multivesicular bodies could secondarily liberate their content in the extracellular space as suggested by the association of cathepsin D with Abeta peptide in the extracellular space.
Langui
Dominique
D
Laboratoire de Neuropathologie Raymond Escourolle, Groupe hospitalier Pitié-Salpêtrière, 47, boulevard de l'Hôpital, 75013 Paris, France.
Girardot
Nadège
N
El Hachimi
Khalid Hamid
KH
Allinquant
Bernadette
B
Blanchard
Véronique
V
Pradier
Laurent
L
Duyckaerts
Charles
C
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D019921:Biotinylation; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002402:Cathepsin D / Q000502:physiology; D000939:Epitopes / Q000737:chemistry; D005838:Genotype; D006056:Golgi Apparatus / Q000378:metabolism; D007150:Immunohistochemistry; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D053764:Presenilin-1; D017434:Protein Structure, Tertiary
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000939:Epitopes; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010455:Peptides; D053764:Presenilin-1; C106354:flotillins; D002402:Cathepsin D