Amyloid beta protein is internalized selectively by hippocampal field CA1 and causes neurons to accumulate amyloidogenic carboxyterminal fragments of the amyloid precursor protein.
A critical issue concerning Alzheimer's disease is its selectivity, which leads to cellular degeneration in certain brain areas but not in others, and whether this pathogenic selectivity involves products of the amyloid precursor protein (APP). Here, we show that the amyloid beta protein Abeta1-42 is accumulated gradually and is retained intact by field CA1, but not by other subdivisions, of organotypic hippocampal slice cultures. In contrast, the slightly shorter Abeta1-40 peptide was not sequestered selectively. Sequestration of Abeta1-42 was followed by the build-up of carboxyterminal fragments of the endogenous precursor protein that were identified by immunoprecipitation. Unlike the peptide uptake, this induction appeared to be stochastic at the cellular level. In addition, the APP fragments were distributed more broadly within the CA1 pyramidal neurons than the sequestered Abeta1-42, and they appeared to be localized to synaptic terminals in the molecular layer of the dentate gyrus and in the stratum lacunosum-moleculare of the subfield CA3. Concentrations of synaptophysin, a presynaptic marker, decreased as the number of neurons producing amyloidogenic species increased. These results indicate that exogenous Abeta1-42 sets into motion a sequence that involves 1) selective uptake of the peptide by vulnerable cells at risk in Alzheimer's disease, 2) markedly enhanced production of amyloidogenic precursor material, and 3) slow deterioration of central synapses.
Bahr
B A
BA
Cortex Pharmaceuticals, Inc., Irvine, California 92618, USA. bahr@uconnvm.uconn.edu
Hoffman
K B
KB
Yang
A J
AJ
Hess
U S
US
Glabe
C G
CG
Lynch
G
G
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002264:Carboxylic Acids; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D013269:Stochastic Processes; D016708:Synaptophysin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002264:Carboxylic Acids; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D016708:Synaptophysin; C075222:amyloid beta-protein (1-42)