Endogenous APP accumulates in synapses after BACE1 inhibition.
Neurosci Res
; 109: 9-15, 2016 Aug.
Article
em En
| MEDLINE
| ID: mdl-26907521
ABSTRACT
BACE1-mediated cleavage of APP is a pivotal step in the production of the Alzheimer related Aß peptide and inhibitors of BACE1 are currently in clinical development for the treatment of Alzheimer disease (AD). While processing and trafficking of APP has been extensively studied in non-neuronal cells, the fate of APP at neuronal synapses and in response to reduced BACE1 activity has not been fully elucidated. Here we examined the consequence of reduced BACE1 activity on endogenous synaptic APP by monitoring N- and C-terminal APP epitopes by immunocytochemistry. In control rodent primary hippocampal neuron cultures, labeling with antibodies directed to N-terminal APP epitopes showed a significant overlap with synaptic vesicle markers (SV2 or synaptotagmin). In contrast, labeling with antibodies directed to C-terminal epitopes of APP showed only a limited overlap with these proteins. In neurons derived from BACE1-deficient mice, and in control neurons treated with a BACE1 inhibitor, both the N-terminal and the C-terminal APP labeling overlapped significantly with synaptic vesicle markers. Moreover, BACE1 inhibition increased the proximity between the APP C-terminus and SV2 as shown by a proximity ligation assay. These results, together with biochemical observations, indicate that BACE1 can regulate the levels of full-length APP at neuronal synapses.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sinapses
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Ácido Aspártico Endopeptidases
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Precursor de Proteína beta-Amiloide
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Secretases da Proteína Precursora do Amiloide
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Neurônios
Limite:
Animals
Idioma:
En
Revista:
Neurosci Res
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Suécia