Fibrillogenesis in Alzheimer's disease of amyloid beta peptides and apolipoprotein E.
A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone produces few amyloid-like fibrils. However, apoE produced only a minimal effect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's disease. When recombinant apoE isoforms were used, apoE4 was more efficient than apoE3 at enhancing amyloid formation. These in vitro observations support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease.
Castano
E M
EM
Department of Pathology, New York University Medical Center, NY 10016.
Prelli
F
F
Wisniewski
T
T
Golabek
A
A
Kumar
R A
RA
Soto
C
C
Frangione
B
B
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001057:Apolipoproteins E / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D003224:Congo Red; D006801:Humans; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000494:pharmacology; D013194:Staining and Labeling
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D011994:Recombinant Proteins; D003224:Congo Red