APOLIPOPROTEIN-E CARBOXYL-TERMINAL FRAGMENTS ARE COMPLEXED TO AMYLOID-A AND AMYLOID-L - IMPLICATIONS FOR AMYLOIDOGENESIS AND ALZHEIMERS-DISEASE

Apolipoprotein E (ApoE) immunoreactivity is consistently present in th e senile plaques and neurofibrillary tangles of Alzheimer's disease (A D) brain. In vitro, apoE, and in particular its apoE4 isoform, can bin d to and promote fibrillogenesis of the amyloid A beta peptide, the ma in constituent of senile plaques. These findings, together with the st rong genetic association between late onset AD and the E4 allele of ap oE, 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 systemi c 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 (A L) fibrils from patients with familial Mediterranean fever and primary amyloidosis, respectively, and studied the association of apoE with A A and AL proteins. In each case, apoE fragments, detected by Western b lot, co-purified with the amyloid fibrils. Microsequencing analysis id entified COOH-terminal fragments of apoE, similar to the 10-kDa fragme nt produced by thrombin digestion that contains the purported binding region to A beta. In vitro co-incubation of AA with purified human apo E 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 ca rboxyl-terminal fragment of apoE is complexed to amyloid fibrils and r esists proteolysis in vivo and 2) apoE may promote amyloidogenesis thr ough a conformation-dependent interaction regardless of the primary st ructure of the amyloid precursors.