Gelsolin inhibits the fibrillization of amyloid beta-protein, and also defibrillizes its preformed fibrils.
Amyloid beta-protein (Abeta) is present in soluble form in the plasma and cerebrospinal fluid (CSF) of normal people and patients with Alzheimer's disease (AD). However, in AD patients, Abeta gets fibrillized as the main constituent of amyloid plaques in the brain. Soluble synthetic Abeta also forms amyloid-like fibrils when it is allowed to age. The mechanism that prevents soluble Abeta from fibrillization in biological fluids is not clear. We recently reported that gelsolin, a secretory protein, binds to Abeta, and that gelsolin/Abeta complex is present in the plasma [V.P.S. Chauhan, I. Ray, A. Chauhan, H.M. Wisniewski, Biochem. Biophys. Res. Commun. 258 (1999) 241-246.]. We now studied the effect of gelsolin on Abeta fibrillization. Congo red staining and electron microscopic examination in negative staining of aged samples of Abeta alone and Abeta incubated with gelsolin showed that gelsolin inhibits the fibrillization of synthetic Abeta 1-40 and Abeta 1-42 at gelsolin to Abeta molar ratio of 1:40. In addition, gelsolin also defibrillized the preformed fibrils of Abeta 1-40 and Abeta 1-42 in a time-dependent manner. These results suggest that gelsolin functions as an anti-amyloidogenic protein in the plasma and CSF, where it prevents Abeta from fibrillization, and helps to maintain it in the soluble form.
Ray
I
I
New York State Institute for Basic Research in Developmental Disabilities 1050 Forest Hill Road, Staten Island, NY, USA.
Chauhan
A
A
Wegiel
J
J
Chauhan
V P
VP
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D000818:Animals; D001704:Biopolymers / Q000037:antagonists & inhibitors / Q000737:chemistry; D002417:Cattle; D003224:Congo Red / Q000737:chemistry; D018260:Gelsolin / Q000494:pharmacology*; D008854:Microscopy, Electron; D016624:Negative Staining; D009454:Neurofibrils / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects
D016229:Amyloid beta-Peptides; D001704:Biopolymers; D018260:Gelsolin; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D003224:Congo Red