A 31 kilodalton beta-protein immunoreactive polypeptide in neuronal lipofuscin.
The beta-protein, a small fibrillar peptide which is the main constituent of the amyloid deposits in senile neuritic plaques and congophilic angiopathy derives by proteolytic cleavage from at least one of three large precursor proteins of 695 to 770 amino acids encoded by a gene on chromosome 21. In the brain the mRNA coding for these predicted proteins has been localized to neurons and non-neuronal cell types. Monoclonal antibodies raised to a synthetic peptide corresponding to residues 1 to 24 of the beta-protein do not only stain the amyloid deposits characteristic for Alzheimer neuropathology, but also neuronal lipofuscin. This material is immunoreactive in every brain area examined (cerebral and cerebellar cortices, basal ganglia, brainstem) and its reactivity is independent from the presence of Alzheimer's disease. At the ultrastructural level immunoreactivity is associated with the proteinaceous matrix part of lipofuscin which does not contain any fibrillar structures. Western blotting of a lipofuscin enriched fraction shows a beta-protein immunoreactive polypeptide migrating at approximately 31 kDa position on SDS-polyacrylamide gel electrophoresis. These results suggest that a large fragment of the amyloid precursor protein (approximately 280 residues) is associated with lipofuscin. Unlike in the microglial cell where the amyloid precursor is processed in a manner to release the beta-protein which forms amyloid fibers, one pathway of its physiological breakdown in the nerve cell seems to yield a large fragment which accumulates on a lipopigment characteristic for normal aging.
Bancher
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C
New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314.
Grundke-Iqbal
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I
Iqbal
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Kim
K S
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Wisniewski
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HM
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides; D004586:Electrophoresis; D006801:Humans; D007150:Immunohistochemistry; D008062:Lipofuscin / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism*; D010860:Pigments, Biological / Q000378:metabolism*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D008062:Lipofuscin; D010860:Pigments, Biological