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P4–030: Scanning tunnelling microscopy of the β–amyloid protein (Aβ) of Alzheimer's disease suggests a model of oligomer assembly
Author(s) -
Aguilar Mibel,
Small David H.,
Martin Lisandra L.,
Mechler Adam,
Losic Dusan
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.2006.05.1768
Subject(s) - oligomer , monomer , fibril , chemistry , amyloid (mycology) , crystallography , biophysics , polymer chemistry , polymer , biochemistry , biology , organic chemistry , inorganic chemistry
and -secretase-dependent proteolytic processing of A precursor protein (APP). A 40 and A 42 compose amyloid plaques and are thought to play a central role in progression of Alzheimer’s disease. Endoplasmic reticulum (ER) chaperones greatly contribute to protein quality control in ER by refolding unfolded proteins. GRP78, one of ER chaperones, was shown to bind to APP, suggesting the contribution of ER chaperones to production of A . Objective and Methods: We here examined the effect of overexpression of various ER chaperones on production of A 40 and A 42 in HEK293 cells, which produce APP. Results and Conclusions: Overexpression of GRP78 suppressed the production of A 40 and A 42 and this suppression was stimulated by co-expression of its co-chaperone ERdj4. ERdj4 binds to GRP78 via its J domain and stimulated the chaperone activity of GRP78. ERdj4 J, mutant ERdj4 lacking the J domain, did not stimulate the activity of GRP78 for A production. On the other hand, suppression of GRP78 expression by siRNA stimulated the production of A 40 and A 42. Furthermore, GRP78 and APP were co-immuno-precipitated with each other. These results suggested that GRP78 directly binds to APP and makes it resistant to proteolysis with secretase, resulting in suppression of the A production. We also examined the effect of other ER chaperones (GRP94, ORP150, calreticulin and calnexin) on production of A and found that these ER chaperones can be divided into three groups. As well as GRP78, over-expression of ORP150 suppressed the production of both A 40 and A 42. Over-expression of calnexin suppressed the production of A 42 but not A 40. On the other hand, production of neither A 42 nor A 40 was suppressed by over-expression of calreticulin or GRP94. These results suggest that some ER chaperones are involved in proteolysis of APP and that non-toxic inducers of ER chaperones may be therapeutically beneficial for Alzheimer’s disease. On the other hand, over-production of APP in cells or addition of synthetic A 40 and A 42 peptides caused up-regulation of ER chaperones, especially GRP78. This up-regulation of ER chaperones seems to contribute to protection of cells against A .