Premium
P4–043: Mechanisms of neuronal amyloidogenesis
Author(s) -
Pitsi Didier,
Towlson Christopher,
Perez Ruth,
Soriano Salvador
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1781
Subject(s) - internalization , lipid raft , endocytosis , amyloid precursor protein , microbiology and biotechnology , intracellular , chemistry , amyloid (mycology) , mutant , alzheimer's disease , biology , biochemistry , cell , signal transduction , medicine , inorganic chemistry , disease , gene
Background: The processing of the amyloid precursor protein (APP) through the amyloidogenic pathway leads to the formation of the amyloid peptide A , which accumulates in the Alzheimer’s disease (AD) brain. The mechanisms of amyloid generation are reasonably well understood in non-neuronal cells, although much less is known of this process in highly differentiated neurons, which are the main source of the A that accumulates in the AD brain. In neurons, APP is present in the plasma membrane, and deletion of its intracellular tail leads to a selective decrease of short A species. This may be due to impaired APP internalization caused by the loss of its endocytosis motif YENP within that tail and/or the loss of interaction with APP modulators such as the Fe65 and X11 proteins. In addition, components of the amyloidogenic machinery reside at the plasma membrane in lipid rafts (LRs), structures proposed to be sites of A generation. Objectives: Here we investigate to what extent, in neuronal cells, internalization of APP via LRs may be necessary to generate extracellular A . In addition, we explore the role of different APP interactors in the amyloidogenic processing of APP. Method: To study the impact of APP internalization and lipid rafts in neuronal amyloidogenesis, we introduced different APP internalization mutants in primary cortical neurons devoid of APP and measured both amyloidogenesis and APP partitioning to lipid rafts. Using different cholestrol depletion strategies, we then examined the involvement of lipid rafts in the trafficking and processing of wildtype APP and its endocytosis and familial AD (FAD) mutants. Finally, we used a knock-in mouse model expressing the M146V FAD mutation of presenilin 1 (PS1) to assess the involvement of PS1 in neuronal APP trafficking and processing through lipid rafts. Results: We have obtained partitioning profiles of APP, its fragments and the amyloidogenic machinery into lipid rafts. We have measured the dependence of these parameters on lipid raft integrity and on APP internalization, as well as the specific impact of both PS1 and APP FAD mutations. Conclusion: Neuronal lipid rafts are a key area where endocytosis-dependent APP amyloidogenic processing takes place.