Meprin ß knockout reduces brain Aß levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease.

ß-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the major described ß-secretase to generate Aß peptides in Alzheimer's disease (AD). However, all therapeutic attempts to block BACE1 activity and to improve AD symptoms have so far failed. A potential candidate for alternative Aß peptides generation is the metalloproteinase meprin ß, which cleaves APP predominantly at alanine in p2 and in this study we can detect an increased meprin ß expression in AD brain. Here, we report the generation of the transgenic APP/lon mouse model of AD lacking the functional Mep1b gene (APP/lon × Mep1b-/-). We examined levels of canonical and truncated Aß species using urea-SDS-PAGE, ELISA and immunohistochemistry in brains of APP/lon mouse × Mep1b-/-. Additionally, we investigated the cognitive abilities of these mice during the Morris water maze task. Aß1-40 and 1-42 levels are reduced in APP/lon mice when meprin ß is absent. Immunohistochemical staining of mouse brain sections revealed that N-terminally truncated Aß2-x peptide deposition is decreased in APP/lon × Mep1b-/- mice. Importantly, loss of meprin ß improved cognitive abilities and rescued learning behavior impairments in APP/lon mice. These observations indicate an important role of meprin ß within the amyloidogenic pathway and Aß production in vivo.

The Swedish dilemma - the almost exclusive use of APPswe-based mouse models impedes adequate evaluation of alternative ß-secretases.

Alzheimer's disease (AD) is the most common form of dementia, however incurable so far. It is widely accepted that aggregated amyloid ß (Aß) peptides play a crucial role for the pathogenesis of AD, as they cause neurotoxicity and deposit as so-called Aß plaques in AD patient brains. Aß peptides derive from the amyloid precursor protein (APP) upon consecutive cleavage at the ß- and γ-secretase site. Hence, mutations in the APP gene are often associated with autosomal dominant inherited AD. Almost thirty years ago, two mutations at the ß-secretase site were observed in two Swedish families (termed Swedish APP (APPswe) mutations), which led to early-onset AD. Consequently, APPswe was established in almost every common AD mouse model, as it contributes to early Aß plaque formation and cognitive impairments. Analyzing these APPswe-based mouse models, the aspartyl protease BACE1 has been evolving as the prominent ß-secretase responsible for Aß release in AD and as the most important therapeutic target for AD treatment. However, with respect to ß-secretase processing, the very rare occurring APPswe variant substantially differs from wild-type APP. BACE1 dominates APPswe processing resulting in the release of Aß1-x, whereas N-terminally truncated Aß forms are scarcely generated. However, these N-terminally truncated Aß species such as Aß2-x, Aß3-x and Aß4-x are elevated in AD patient brains and exhibit an increased potential to aggregate compared to Aß1-x peptides. Proteases such as meprin ß, cathepsin B and ADAMTS4 were identified as alternative ß-secretases being capable of generating these N-terminally truncated Aß species from wild-type APP. However, neither meprin ß nor cathepsin B are capable of generating N-terminally truncated Aß peptides from APPswe. Hence, the role of BACE1 for the Aß formation during AD might be overrepresented through the excessive use of APPswe mouse models. In this review we critically discuss the consideration of BACE1 as the most promising therapeutic target. Shifting the focus of AD research towards alternative ß secretases might unveil promising alternatives to BACE1 inhibitors constantly failing in clinical trials due to ineffectiveness and harmful side effects.

Regulation of the alternative ß-secretase meprin ß by ADAM-mediated shedding.

Alzheimer's Disease (AD) is the sixth-leading cause of death in industrialized countries. Neurotoxic amyloid-ß (Aß) plaques are one of the pathological hallmarks in AD patient brains. Aß accumulates in the brain upon sequential, proteolytic processing of the amyloid precursor protein (APP) by ß- and γ-secretases. However, so far disease-modifying drugs targeting ß- and γ-secretase pathways seeking a decrease in the production of toxic Aß peptides have failed in clinics. It has been demonstrated that the metalloproteinase meprin ß acts as an alternative ß-secretase, capable of generating truncated Aß2-x peptides that have been described to be increased in AD patients. This indicates an important ß-site cleaving enzyme 1 (BACE-1)-independent contribution of the metalloprotease meprin ß within the amyloidogenic pathway and may lead to novel drug targeting avenues. However, meprin ß itself is embedded in a complex regulatory network. Remarkably, the anti-amyloidogenic α-secretase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a direct competitor for APP at the cell surface, but also a sheddase of inactive pro-meprin ß. Overall, we highlight the current cellular, molecular and structural understanding of meprin ß as alternative ß-secretase within the complex protease web, regulating APP processing in health and disease.