A combination Alzheimer's therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice.

Latha Devi,Masuo Ohno

doi:10.1186/s13041-015-0110-5

Abstract

BackgroundAccumulating evidence indicates that partial inhibition of β-site APP-cleaving enzyme 1 (BACE1), which initiates amyloid-β (Aβ) production, mitigates Alzheimer’s disease (AD)-like pathologies and memory deficits in a battery of transgenic mouse models. However, our previous investigations suggest that therapeutic BACE1 suppression may be beneficial only if targeted on earlier stages of AD and encounter dramatic reductions in efficacy during disease progression. This study was designed to test the possibility that a combination approach, aimed at inhibiting BACE1 and boosting neprilysin (a major Aβ-degrading enzyme) activities, may be able to mechanistically overcome the limited efficacy of anti-Aβ therapy in advanced AD.ResultsAfter crossbreeding between BACE1 heterozygous knockout (BACE1+/−), neprilysin transgenic (NEP) and 5XFAD mice, we analyzed the resultant mice at 12 months of age when 5XFAD controls showed robust amyloid-β (Aβ) accumulation and elevation of BACE1 expression (~2 folds). Although haploinsufficiency lowered BACE1 expression by ~50% in concordance with reduction in gene copy number, profound β-amyloidosis, memory deficits and cholinergic neuron death were no longer rescued in BACE1+/− · 5XFAD mice concomitant with their persistently upregulated BACE1 (i.e., equivalent to wild-type control levels). Notably, neprilysin overexpression not only prevented Aβ accumulation but also suppressed the translation initiation factor eIF2α-associated elevation of BACE1 and lowered levels of the β-secretase-cleaved C-terminal fragment of APP (C99) in NEP · 5XFAD mice. Interestingly, these markers for β-amyloidogenesis in BACE1+/− · NEP · 5XFAD mice were further reduced to the levels reflecting a combination of single BACE1 allele ablation and the abolishment of translational BACE1 upregulation. However, since neprilysin overexpression was striking (~8-fold relative to wild-type controls), memory impairments, cholinergic neuronal loss and β-amyloidosis were similarly prevented in NEP · 5XFAD and BACE1+/− · NEP · 5XFAD mice.ConclusionsOur findings indicate that robust overexpression of neprilysin is sufficient to ameliorate AD-like phenotypes in aged 5XFAD mice. We also found that Aβ-degrading effects of overexpressed neprilysin can block deleterious BACE1-elevating mechanisms that accelerate Aβ production, warranting further study to test whether interventions moderately activating neprilysin may be useful for boosting the limited efficacy of therapeutic BACE1 inhibition in treating AD with established Aβ pathology.

Highlights

Accumulating evidence indicates that partial inhibition of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), which initiates amyloid-β (Aβ) production, mitigates Alzheimer’s disease (AD)-like pathologies and memory deficits in a battery of transgenic mouse models
The degrees of Aβ reductions, mnemonic amelioration and neuronal protection were indistinguishable between neprilysin transgenic (NEP) · 5XFAD and BACE1+/− · NEP · 5XFAD mice, we found the advantage of combining BACE1 haploinsufficiency and neprilysin overexpression in more robustly suppressing the β-amyloidogenic processing of APP
The present study shows that transgenic overexpression of neprilysin is sufficient to reduce Aβ accumulation and almost completely prevent cholinergic neuron loss and memory deficits in aged 5XFAD mice

Summary

Introduction

Accumulating evidence indicates that partial inhibition of β-site APP-cleaving enzyme 1 (BACE1), which initiates amyloid-β (Aβ) production, mitigates Alzheimer’s disease (AD)-like pathologies and memory deficits in a battery of transgenic mouse models. BACE1 haploinsufficiency (BACE1+/−; i.e., a therapeutic relevant model for 50% suppression) [12,13,14,15,16,17,18] as well as chronic treatments with bioavailable small-molecule BACE1 inhibitors (e.g., GRL-8234 and TAK-070) [19,20,21] has been reported to partially reduce cerebral Aβ concentrations and mitigate amyloid plaque and tau pathologies, cholinergic neuron loss, mitochondrial dysfunction, hippocampal synaptic failure, and memory deficits in APP mice Some of these studies raise concern that the beneficial outcomes associated with partial BACE1 inhibition may decline during the progression of AD [11,12,15,16,18,21]. We tested whether a combination strategy that boosts Aβ degradation (neprilysin overexpression) and arrests Aβ production (BACE1 haploinsufficiency) may be useful for mechanistically increasing the limited therapeutic efficacies in 12-month-old 5XFAD mice

Methods

Results

Discussion

Conclusion