Low molecular weight Abeta induces collapse of endoplasmic reticulum.
The endoplasmic reticulum (ER) is a dynamic multifunction organelle that is responsible for Ca(2+) homeostasis, protein folding, post-translational modification, protein degradation, and transportation of nascent proteins. Disruption of ER architecture might affect the normal physiology of the cell. In yeast, expansion of the ER is observed under unfolded protein response (UPR) and subsequently induces autophagy initiated from the ER. Here, we found that soluble low molecular weight of Abeta disrupted the anchoring between ER and microtubules (MT) and induced collapse of ER. In addition, it decreased the stability of MT. Subsequently, low molecular weight Abeta triggered autophagy and enhanced lysosomal degradation, as shown by electron microscopy and live-cell imaging. Dysfunction of ER can be further proved in postmortem AD brain and transgenic mice bearing APP Swedish mutation by immunohistochemical analysis of calreticulin. Treatment with Taxol, a MT-stabilizing agent, could partially inhibit collapse of the ER and induction of autophagy. The results show that Abeta-induced disruption of MT can affect the architecture of the ER. Collapse/aggregation of the ER may play an important role in Abeta peptide-triggered neurodegenerative processes.
Lai
Cora Sau-Wan
CS
Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong, L1-49, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.
Preisler
Julie
J
Baum
Larry
L
Lee
Daniel Hong-Seng
DH
Ng
Ho-Keung
HK
Hugon
Jacques
J
So
Kwok-Fai
KF
Chang
Raymond Chuen-Chung
RC
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D008970:Molecular Weight; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D015739:Nocodazole / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D011993:Recombinant Fusion Proteins; D014404:Tubulin; D050257:Tubulin Modulators; D015739:Nocodazole