Intracellular sAPP retention in response to Abeta is mapped to cytoskeleton-associated structures.
Amyloid beta (Abeta) contributes to neurodegeneration in Alzheimer's disease and provides a close association between molecular events and pathology, although the underlying molecular mechanisms are unclear. In the work described here, Abeta did not induce amyloid precursor protein (APP) expression, but APP processing/trafficking was markedly affected. In COS-7 cells, Abeta provokes retention of intracellular sAPPalpha (isAPPalpha). Intracellular holo-APP levels remain unchanged, and extracellular total sAPP increases, although extracellular sAPPalpha alone was not altered significantly. In primary neuronal cultures and PC12 cells, isAPP also increased, but this was mirrored by a decrease in extracellular total sAPP. The isAPP retention was particularly associated with the cytoskeletal fraction. The retention "per se" occurred in vesicular-like densities, negative for a C-terminal antibody and strongly positive for the 6E10 antibody, clearly showing abnormal intracellular accumulation of sAPPalpha in response to Abeta. Our data support a dynamic model for intracellular retention of sAPPalpha as an early response to Abeta exposure. Particularly noteworthy was the observation that removal of Abeta reversed the isAPP accumulation. Mechanistically, these findings disclose an attractive physiological response, revealing the capacity of cells to deal with adverse effects induced by Abeta.
Henriques
Ana Gabriela
AG
Laboratório de Neurociências, Centro de Biologia Celular, Universidade de Aveiro, Aveiro, Portugal.
Vieira
Sandra Isabel
SI
Crespo-López
Maria Elena
ME
Guiomar de Oliveira
Márcio A
MA
da Cruz e Silva
Edgar F
EF
da Cruz e Silva
Odete A B
OA
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015152:Blotting, Northern; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003599:Cytoskeleton / Q000378:metabolism*; D015870:Gene Expression; D007150:Immunohistochemistry; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D012313:RNA / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D012313:RNA