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Sci Rep ; 9(1): 19877, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882662

RESUMO

BACE1 is the first enzyme involved in APP processing, thus it is a strong therapeutic target candidate for Alzheimer's disease. The observation of deleterious phenotypes in BACE1 Knock-out (KO) mouse models (germline and conditional) raised some concerns on the safety and tolerability of BACE1 inhibition. Here, we have employed a tamoxifen inducible BACE1 conditional Knock-out (cKO) mouse model to achieve a controlled partial depletion of BACE1 in adult mice. Biochemical and behavioural characterization was performed at two time points: 4-5 months (young mice) and 12-13 months (aged mice). A ~50% to ~70% BACE1 protein reduction in hippocampus and cortex, respectively, induced a significant reduction of BACE1 substrates processing and decrease of Aßx-40 levels at both ages. Hippocampal axonal guidance and peripheral nerve myelination were not affected. Aged mice displayed a CA1 long-term potentiation (LTP) deficit that was not associated with memory impairment. Our findings indicate that numerous phenotypes observed in germline BACE1 KO reflect a fundamental role of BACE1 during development while other phenotypes, observed in adult cKO, may be absent when partially rather than completely deleting BACE1. However, we demonstrated that partial depletion of BACE1 still induces CA1 LTP impairment, supporting a role of BACE1 in synaptic plasticity in adulthood.


Assuntos
Secretases da Proteína Precursora do Amiloide/deficiência , Ácido Aspártico Endopeptidases/deficiência , Orientação de Axônios/genética , Região CA1 Hipocampal , Córtex Cerebral , Deleção de Genes , Plasticidade Neuronal/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Região CA1 Hipocampal/enzimologia , Região CA1 Hipocampal/patologia , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Camundongos , Camundongos Knockout
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