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From the Neuropathology Laboratory,* La Salpêtrière Hospital, Assistance Publique-Hopitaux de Paris, Paris VI University, Paris; Aventis Pharma, ¶ Central Nervous System/Alzheimer Group, Vitry; Inserm U289, Paris; Ecole Pratique des Hautes Etudes, Paris; and InsermU573, Centre Paul Broca, Paris, France
In transgenic mice expressing human mutant ß-amyloid precursor protein (APP) and mutant presenilin-1 (PS1), Aß antibodies labeled granules, about 1 µm in diameter, in the perikaryon of neurons clustered in the isocortex, hippocampus, amygdala, thalamus, and brainstem. The granules were present before the onset of Aß deposits; their number increased up to 9 months and decreased in 15-month-old animals. They were immunostained by antibodies against Aß 40, Aß 42, and APP C-terminal region. In double immunofluorescence experiments, the intracellular Aß co-localized with lysosome markers and less frequently with MG160, a Golgi marker. Aß 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, Aß, APP-C terminal, cathepsin D, and flotillin-1 epitopes were found in the lumen of multivesicular bodies. This study shows that Aß 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 Aß peptide in the extracellular space.
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