Effects of acidosis on the distribution of processing of the beta-amyloid precursor protein in cultured hippocampal neurons.
Reported increases in brain lactate production in Alzheimer disease led us to test the hypothesis that lactic acid acidosis alters the processing of the beta-amyloid precursor protein, beta PP, in neurons. To test this proposition, embryonic rat hippocampal neurons were first cultures for 4 d in serum-free B27/neurobasal medium. Lactic acid at 0.5 and 1 mg/mL (pH 7.1 and, 6.9, respectively) caused a dose-dependent increase in cellular beta-amyloid immunoreactivity detected with antibody 4G8. Acidosis did not affect secretion of beta PP or its derivatives into the medium. The cytoplasmic production of beta PP was slightly reduced by acidosis without a differential effect on maturation or proteolytic processing. In the substrate-bound material, which was insoluble in nonionic detergent, acidosis caused increases in an N-terminal 75-kDa band, a C-terminal 72-kDa band, and potentially amyloidogenic bands at 35 and 38 kDa. Processing to the 4-kDa amyloid beta protein was not observed in these early pure rat neuronal cultures. These results suggest that mild acidosis id sufficient to alter neuronal processing to the amyloid precursor protein into potentially amyloidogenic forms and increase certain beta PP fragments bound to the substrate. If a similar process occurs in the presence of other cell types in the aging brain, acidosis may stimulate an extracellular deposition of amyloid and contribute to the pathogenesis of Alzheimer disease.
Brewer
G J
GJ
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield 62794-1220, USA. gbrewer@siumed.edu
D000140:Acidosis, Lactic / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D003470:Culture Media; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016564:Amyloid beta-Protein Precursor; D003470:Culture Media