Apolipoprotein E carboxyl-terminal fragments are complexed to amyloids A and L. Implications for amyloidogenesis and Alzheimer's disease.
Apolipoprotein E (ApoE) immunoreactivity is consistently present in the senile plaques and neurofibrillary tangles of Alzheimer's disease (AD) brain. In vitro, apoE, and in particular its apoE4 isoform, can bind to and promote fibrillogenesis of the amyloid A beta peptide, the main constituent of senile plaques. These findings, together with the strong genetic association between late onset AD and the E4 allele of apoE, have strengthened the hypothesis that apoE may have a central role in the pathogenesis of AD by modulating A beta cerebral accumulation. However, apoE immunoreactivity is present in all cerebral and systemic amyloidoses tested, and tryptic apoE fragments have been identified in association with amyloid A (AA). In order to further elucidate the interaction between apoE and amyloids, we purified AA and amyloid L (AL) fibrils from patients with familial Mediterranean fever and primary amyloidosis, respectively, and studied the association of apoE with AA and AL proteins. In each case, apoE fragments, detected by Western blot, co-purified with the amyloid fibrils. Microsequencing analysis identified COOH-terminal fragments of apoE, similar to the 10-kDa fragment produced by thrombin digestion that contains the purported binding region to A beta. In vitro co-incubation of AA with purified human apoE resulted in the formation of an SDS-resistant AA.apoE complex and a higher degree of polymerization of the AA peptide. These findings and similar results obtained from AD senile plaques suggest that 1) the carboxyl-terminal fragment of apoE is complexed to amyloid fibrils and resists proteolysis in vivo and 2) apoE may promote amyloidogenesis through a conformation-dependent interaction regardless of the primary structure of the amyloid precursors.
Castaño
E M
EM
Department of Pathology, New York University Medical Center, New York 10016, USA.
Prelli
F
F
Pras
M
M
Frangione
B
B
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis / Q000737:chemistry*; D001057:Apolipoproteins E / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*
D000682:Amyloid; D001057:Apolipoproteins E; D010446:Peptide Fragments