The role of meprin β for the pathogenesis of Alzheimer's disease

Alzheimer’s disease (AD) is the most common type of dementia, however, incurable thus far. The release of neurotoxic amyloid-β (Aβ) peptides, which are generated from the amyloid precursor protein (APP) upon cleavage at the β- and γ-secretase sites, play a central role for neurodegeneration in AD. Since the β-site of APP cleaving enzyme (BACE1) was identified as the major β-secretase, it was considered as one of the most promising therapeutic targets for AD treatment. However, so far every BACE1 inhibitor failed in clinical trials. Interestingly, besides the conventional Aβ peptides, also N-terminally truncated Aβ species such as Aβ2-42 were identified to be elevated in AD patient brains. Taking into account that BACE1 is not involved in the generation of these truncated Aβ species, the characterization of alternative β-secretases is of interest for AD research. The metalloprotease meprin β is upregulated in AD patient brains, capable of cleaving APP and thereby releasing N-terminally truncated Aβ. This thesis aimed to provide deeper insight into the mechanistic regulation of APP processing by meprin β and to evaluate the in vivo role of meprin β in AD using different mouse models. Analyzing the regulation of meprin β, C-terminal phosphorylation of meprin β was found to diminish its surface activity and leads to decreased APP processing. Moreover, a bacterial protease arginine-gingipain B (RgpB) was characterized as meprin β activator promoting amyloidogenic APP processing. Furthermore, meprin β was observed to diminish the phagocytic potential of myeloid cells by shedding the cells surface receptor triggering receptor expressed on myeloid cells 2 (TREM2). This might reduce the capability of Aβ uptake by microglia. In order to evaluate the in vivo relevance of meprin β for AD, mice expressing the London APP (APPlon) variant were crossed with meprin β knock-out mice and characterized with regard to AD-like pathology. Of note, the amyloid phenotype of the APPlon mice was markedly reduced and cognitive impairments were completely recovered, when meprin β was abolished. Therefore, a crucial in vivo role of meprin β in AD was hypothesized. As meprin β is upregulated in AD patient brains, another approach was the overexpression of meprin β in wild-type mouse brains. Since astrocytes were previously identified to produce Aβ2-42 rather than other brain cell types, meprin β was conditionally overexpressed in astrocytes. Intriguingly, amyloidogenic APP processing and Aβ release were elevated in these mice. Therefore, meprin β emerges as a promising target for inhibitor application to prevent from the generation of Aβ, which may serve as therapeutic approach for AD treatment. Beyond APP as a substrate, N-terminomic analyses of mice overexpressing meprin β in astrocytes revealed several new candidate substrates of meprin β. In summary, this thesis further enlightens the mechanistic regulation of APP cleavage by meprin β and provides evidence for an in vivo role of meprin β for the pathogenesis of AD.


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