Amyloid precursor protein expression in the rat hippocampal dentate gyrus modulates during memory consolidation.
Despite advances in our understanding of the basic biology of amyloid precursor protein (APP), the normal physiological function(s) of APP in learning and memory remains unclear. Here we show increased APP degradation in the hippocampus to be associated with the consolidation of a passive avoidance response. Neurone-specific APP695 expression became transiently reduced 2-4 h post-training through association with endosomal adaptin proteins and enhanced internalization. By contrast, internalization of glial-associated APP containing a Kunitz protease inhibitor-like domain (APP-KPI) was dependent on the low-density lipoprotein receptor-related protein (LRP). In addition, LRP expression and association with apolipoprotein E increased in the 2-4 h post-training period. The LRP antagonist receptor-associated protein prevented the APP-KPI internalization and LRP-apolipoprotein E association and this resulted in amnesia. Degradation of APP695 and APP-KPI did not appear to be related to alpha-secretase activity, as no learning-associated increase of secreted APP was observed in the CSF. Moreover, as internalization of APP isoforms was observed only in dentate gyrus, it probably relates to the learning-associated restructuring of the perforant path terminals. Memory-associated APP processing in both neuronal and glial compartments points to a role for glial unsheathing of synaptic connections, an event required for the synaptic restructuring that accompanies memory consolidation. These observations may have a direct relevance to understanding the pathophysiology of Alzheimer's disease as beta/gamma-secretase-derived beta-amyloid is formed following internalization of cell surface APP into the endosomal compartment.
Conboy
Lisa
L
Applied Neurotherapeutics Research Group, Department of Pharmacology, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Murphy
Keith J
KJ
Regan
Ciaran M
CM
D034001:Adaptor Protein Complex Subunits / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000134:cerebrospinal fluid; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D007611:Aprotinin / Q000378:metabolism; D001362:Avoidance Learning / Q000502:physiology; D015153:Blotting, Western; D018891:Dentate Gyrus / Q000378:metabolism* / Q000502:physiology*; D004591:Electrophoresis, Polyacrylamide Gel; D004705:Endocytosis / Q000187:drug effects; D007276:Injections, Intraventricular; D026502:LDL-Receptor Related Proteins / Q000037:antagonists & inhibitors; D008297:Male; D008568:Memory / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism
D034001:Adaptor Protein Complex Subunits; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D026502:LDL-Receptor Related Proteins; D011994:Recombinant Proteins; C098973:recombinant Kunitz protease inhibitor; D007611:Aprotinin