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

Alzheimer's disease (AD) is the most common form of dementia, however incurable so far. It is widely accepted that aggregated amyloid beta (A beta) peptides play a crucial role for the pathogenesis of AD, as they cause neurotoxicity and deposit as so-called A beta plaques in AD patient brains. A beta peptides derive from the amyloid precursor protein (APP) upon consecutive cleavage at the beta- and gamma-secretase site. Hence, mutations in the APP gene are often associated with autosomal dominant inherited AD. Almost thirty years ago, two mutations at the beta-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 A beta plaque formation and cognitive impairments. Analyzing these APPswe-based mouse models, the aspartyl protease BACE1 has been evolving as the prominent beta-secretase responsible for A beta release in AD and as the most important therapeutic target for AD treatment. However, with respect to beta-secretase processing, the very rare occurring APPswe variant substantially differs from wild-type APP. BACE1 dominates APPswe processing resulting in the release of A beta 1-x, whereas N-terminally truncated A beta forms are scarcely generated. However, these N-terminally truncated AP species such as A beta 2-x, A beta 3-x and A beta 4-x are elevated in AD patient brains and exhibit an increased potential to aggregate compared to A beta 1-x peptides. Proteases such as meprin beta, cathepsin B and ADAMTS4 were identified as alternative beta-secretases being capable of generating these Nterminally truncated A beta species from wild-type APP. However, neither meprin beta nor cathepsin B are capable of generating N-terminally truncated A beta peptides from APPswe. Hence, the role of BACE1 for the A beta 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 beta secretases might unveil promising alternatives to BACE1 inhibitors constantly failing in clinical trials due to ineffectiveness and harmful side effects.

Automated summary

Alzheimer's disease is the most common form of dementia and currently incurable. The discovery of the APPswe mutation, which is associated with early-onset AD, has shed light on the role of beta-secretase in AD pathogenesis. However, alternative beta-secretases have also been identified, suggesting that shifting the focus of AD research towards these alternatives may lead to new therapeutic targets.