K. Ueda et al., MOLECULAR-CLONING OF CDNA-ENCODING AN UNRECOGNIZED COMPONENT OF AMYLOID IN ALZHEIMER-DISEASE, Proceedings of the National Academy of Sciences of the United Statesof America, 90(23), 1993, pp. 11282-11286
A neuropathological hallmark of Alzheimer disease (AD) is a widespread
amyloid deposition. We analyzed the entire amino acid sequences in an
amyloid preparation and found, in addition to the major beta/A4-prote
in (Abeta) fragment, two unknown peptides. We raised antibodies agains
t synthetic peptides using subsequences of these peptides. These antib
odies immunostained amyloid in neuritic and diffuse plaques as well as
vascular amyloid. Electron microscopic analysis demonstrated that the
immunostaining was localized on amyloid fibrils. We have isolated an
apparently full-length cDNA encoding a 140-amino-acid protein within w
hich two previously unreported amyloid sequences are encoded in tandem
in the most hydrophobic domain. We tentatively named this 35-amino ac
id peptide NAC (non-Abeta component of AD amyloid) and its precursor N
ACP. NAC is the second component, after Abeta, identified chemically i
n the purified AD amyloid preparation. Secondary structure predictions
indicate that the NAC peptide sequence has a strong tendency to form
beta-structures consistent with its association with amyloid. NACP is
detected as a M(r) 19,000 protein in the cytosolic fraction of brain h
omogenates and comigrates on immunoblots with NACP synthesized in Esch
erichia coli from NACP cDNA. NACP mRNA is expressed principally in bra
in but is also expressed in low concentrations in all tissues examined
except in liver, suggesting its ubiquitous and brain-specific functio
ns. The availability of the cDNA encoding full-length NACP should help
to elucidate the mechanisms of amyloidosis in AD.