BACE1 (β-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time

Abstract

The formation of Alzheimer's Aβ peptide is initiated when the amyloid precursor protein (APP) is cleaved by the enzyme β-secretase (BACE1); inhibition of this cleavage has been proposed as a means of treating Alzheimer's disease. (AD) We have previously shown that young BACE1 knockout mice (BACE1 KO) do not generate Aβ but in other respects appear normal. Here we have extended this analysis to include both gene expression profiling and phenotypic assessment of older BACE1 KO animals to evaluate the impact of chronic Aβ deficiency. We did not detect global compensatory changes in neural gene expression in young BACE1 KO mice. In particular, expression of the β-secretase homolog BACE2 was not upregulated. Furthermore, we found no structural alterations in any organ, including all central and peripheral neural tissues, of BACE1 KO mice up to 14 months of age. Aged BACE1 KO mice engineered to overexpress human APP (BACE1 KO/APPtg) did not develop amyloid plaques. These data provide evidence that neither β-secretase nor Aβ plays a vital role in mouse physiology and that chronic β-secretase inhibition could be a useful approach in treating AD.

Introduction

At present, the generation of amyloid β-peptide (Aβ) is widely held to play an early and critical role in the pathogenesis of Alzheimer's disease (Hardy and Selkoe, 2002). Consequently, the mechanisms of Aβ generation and clearance have attracted considerable attention, both from the standpoint of basic scientific understanding and from a therapeutic perspective.

Aβ is generated from the large precursor protein amyloid precursor protein (APP) by the sequential action of two proteases, β- and γ-secretase. β-Secretase has been identified as β-site APP-cleaving enzyme 1 (BACE1) which, together with its homolog BACE2, forms a novel subfamily of transmembrane aspartic proteases within the pepsin family (for review, see Vassar and Citron, 2000). We and others have recently demonstrated that young BACE1 knockout mice (BACE1 KO or −/− mice) fail to generate Aβ but appear to be normal in other respects Cai et al., 2001, Luo et al., 2001, Roberds et al., 2001.

In the present work, we have extended our analysis of BACE1 KO mice in two important ways. First, we used gene expression profiling to explore the potential for compensatory changes in neural genes that could contribute to the “normal” phenotype in young mice. Our findings show that global gene expression in brain is not changed in BACE1 KO mice and in particular that the homolog BACE2 is not upregulated in the absence of BACE1. Second, we investigated the impact of chronic BACE1 blockade by performing detailed anatomic and clinical pathology assessments on aged BACE1 KO mice. Our data indicate that neither functional nor structural alterations—including amyloid plaques or other neural lesions—develop over time. Taken together, these facts show that (1) BACE1 expression is critical for formation of both Aβ and amyloid plaques and (2) the extended absence of BACE1 and Aβ does not result in major neural or systemic side effects in our mice that would rule out BACE1 inhibitors as potential agents to treat or prevent Alzheimer's disease.