The molecular chaperone alphaB-crystallin enhances amyloid beta neurotoxicity.
Amyloid beta (Abeta) is a 40- to 42-residue peptide that is implicated in the pathogenesis of Alzheimer's Disease (AD). As a result of conformational changes, Abeta assembles into neurotoxic fibrils deposited as 'plaques' in the diseased brain. In AD brains, the small heat shock proteins (sHsps) alphaB-crystallin and Hsp27 occur at increased levels and colocalize with these plaques. In vitro, sHsps act as molecular chaperones that recognize unfolding peptides and prevent their aggregation. The presence of sHsps in AD brains may thus reflect an attempt to prevent amyloid fibril formation and toxicity. Here we report that alphaB-crystallin does indeed prevent in vitro fibril formation of Abeta(1-40). However, rather than protecting cultured neurons against Abeta(1-40) toxicity, alphaB-crystallin actually increases the toxic effect. This indicates that the interaction of alphaB-crystallin with conformationally altering Abeta(1-40) may keep the latter in a nonfibrillar, yet highly toxic form.
Stege
G J
GJ
Department of Biochemistry, Institute of Neurology, University of Nijmegen, Nijmegen, 6500 HB, The Netherlands.
Renkawek
K
K
Overkamp
P S
PS
Verschuure
P
P
van Rijk
A F
AF
Reijnen-Aalbers
A
A
Boelens
W C
WC
Bosman
G J
GJ
de Jong
W W
WW
D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex; D003459:Crystallins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus; D018832:Molecular Chaperones / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D051381:Rats; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D003459:Crystallins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T