Increasing neurite outgrowth capacity of beta-amyloid precursor protein proteoglycan in Alzheimer's disease

Progressive cerebral deposition of beta-amyloid peptide either in blood ves sels or around neurites is one of the most important features of Alzheimer' s disease (AD), The beta-peptide, known as A beta or A4, is produced by pro teolytic cleavage of the amyloid precursor protein (APP). Two APP processin g pathways have been proposed as physiological alternatives; only one of wh ich leads to the production of A beta or amyloidogenic peptides. However, w e have little information regarding these processing pathways in the brain, or on whether posttranslational modifications such as glycosylation affect APP processing in vivo. Furthermore, the physiological function(s) of this protein in nervous tissue remains unclear, although modulatory roles in ce ll adhesion and neuritic extension have been suggested. It has been reporte d that APP may be glycosylated as a proteoglycan. We purified this APP popu lation from human brain, and our data indicate that PG-APP supports neurite extension of hippocampal neurons. Neurons grown on this substratum showed an increased capacity to elongate neurites and increased neuritic "branchin g" compared to culture on laminin. These effects were enhanced with PG-APP samples obtained from AD brains. Our results suggest that this APP populati on may act as a neurite outgrowth and branching promoter and may thus play a role in some pathological conditions. These findings may have significant implications in understanding normal brain development and pathological si tuations (such as AD). J. Neurosci. Res. 60:87-97, 2000. (C) 2000 Wiley-Lis s, Inc.