Raft disorganization leads to reduced plasmin activity in Alzheimer's disease brains.
The serine protease plasmin can efficiently degrade amyloid peptide in vitro, and is found at low levels in the hippocampus of patients with Alzheimer's disease (AD). The cause of such paucity remains unknown. We show here that the levels of total brain plasminogen and plasminogen-binding molecules are normal in these brain samples, yet plasminogen membrane binding is greatly reduced. Biochemical analysis reveals that the membranes of these brains have a mild, still significant, cholesterol reduction compared to age-matched controls, and anomalous raft microdomains. This was reflected by the loss of raft-enriched proteins, including plasminogen-binding and -activating molecules. Using hippocampal neurons in culture, we demonstrate that removal of a similar amount of membrane cholesterol is sufficient to induce raft disorganization, leading to reduced plasminogen membrane binding and low plasmin activity. These results suggest that brain raft alterations may contribute to AD by rendering the plasminogen system inefficient.
Ledesma
Maria Dolores
MD
Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, A.O. San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano (TO), Italy.
Abad-Rodriguez
José
J
Galvan
Cristian
C
Biondi
Elisa
E
Navarro
Pilar
P
Delacourte
Andre
A
Dingwall
Colin
C
Dotti
Carlos G
CG
D033982:Adaptor Protein Complex gamma Subunits / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D005341:Fibrinolysin / Q000032:analysis / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism; D013997:Time Factors; D014020:Tissue Extracts / Q000737:chemistry / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
D033982:Adaptor Protein Complex gamma Subunits; D016229:Amyloid beta-Peptides; D014020:Tissue Extracts; D014404:Tubulin; D010958:Plasminogen; D002784:Cholesterol; D012697:Serine Endopeptidases; D005341:Fibrinolysin