BACE1 partial deletion induces synaptic plasticity deficit in adult mice

Sylvia Lombardo,Thomas W Rosahl,Philip G Haydon,Martina Chiacchiaretta,Giuseppina Tesco,Matthew E Kennedy,Andrew Tarr,Wonhee Kim,Griffin Sigal,Weiming Xia,Tingyi Cao

doi:10.1038/s41598-019-56329-7

Abstract

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 Aβx-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.

Highlights

BACE1 is the first enzyme involved in amyloid precursor protein (APP) processing, it is a strong therapeutic target candidate for Alzheimer’s disease
BACE1 mRNA levels were decreased in cortex, hippocampus and cerebellum of young TAM-treated mice compared to controls (Supplementary Fig. 2) (VEH-cortex:[1]; TAM-cortex:0.31; VEH-treated mice (VEH)-hippocampus:[1], TAMhippocampus:0.50; VEH-cerebellum:[1]; TAM-cerebellum:0.32; expressed as fold-change; VEH n = 9; TAM n = 9; p < 0.0001)
Protein level of BACE1 were not altered in cortex of BACE1flox/flox TAM-treated compared to untreated WT mice, indicating that the decrease in BACE1flox/flox;RosaCreERT2+/WT was due to the recombination (Supplementary Fig. 3) (BACE1flox/flox:0.91 ± 0.03, n = 6; WT:1 ± 0.08, n = 5; ns)

Summary

Introduction

BACE1 is the first enzyme involved in APP processing, it is a strong therapeutic target candidate for Alzheimer’s disease. We www.nature.com/scientificreports hypothesized that a lower level of BACE1 depletion may not result in negative phenotypes while still eliciting inhibition of CNS Aβ To test this hypothesis, we achieved a partial deletion of BACE1 in a cKO mouse model and we characterized mice following both short-term acute depletion and long-term, prolonged depletion of BACE1. Mice were characterized at two time points: 4–5 months (young) and 12–13 months (aged) corresponding to 1 and 10 months after cessation of TAM treatment respectively In both investigated cohorts we detected reduced processing of multiple BACE1 substrates and a 50% decrease in Aβx-40 levels. Hippocampal axonal guidance and peripheral nerve myelination were not affected, in aged mice we observed an LTP deficit in the CA1 region of the hippocampus that was not associated with a memory impairment in the behavioural tests investigated (Y maze and contextual fear conditioning). We demonstrated that a partial depletion of BACE1 still induces CA1 LTP impairment, supporting a role of BACE1 in synaptic plasticity in adulthood

Methods

Results

Conclusion