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At the origin of Aβ with ADAM10
Intracellular accumulation of insoluble amyloid β peptide (Aβ) oligomers is a major pathogenic event in Alzheimer’s disease (AD). Cleavage of APP by β- and γ-secretases generates insoluble Aβ peptides. On the contrary, α-secretase cleaves APP to form sAPPα, a soluble, neuroprotective fragment. ADAM10, a major α-secretase, is thought to play a role in AD; however, the mechanisms mediating ADAM10 modulation are unclear. Here, Nakamura et al. show that the ADAM10 inhibitor RECK is increased in human AD brain samples. The authors found that RECK is controlled by GDE2 and GDE2 ablation or RECK elevation in mice promoted insoluble Aβ oligomer formation and accelerated AD pathology. Targeting this pathway might reduce Aβ pathology in AD.
Abstract
A disintegrin and metalloprotease 10 (ADAM10) is the α-secretase for amyloid precursor protein (APP). ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ, a defining feature of Alzheimer’s disease (AD) pathophysiology. Reduced ADAM10 activity is implicated in AD, but the mechanisms mediating ADAM10 modulation are unclear. We find that the plasma membrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2) stimulates ADAM10 APP cleavage by shedding and inactivating reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol (GPI)–anchored inhibitor of ADAM10. In AD, membrane-tethered RECK is highly elevated and GDE2 is abnormally sequestered inside neurons. Genetic ablation of GDE2 phenocopies increased membrane RECK in AD, which is causal for reduced sAPPα, increased Aβ, and synaptic protein loss. RECK reduction restores the balance of APP processing and rescues synaptic protein deficits. These studies identify GDE2 control of RECK surface activity as essential for ADAM10 α-secretase function and physiological APP processing. Moreover, our results suggest the involvement of the GDE2-RECK-ADAM10 pathway in AD pathophysiology and highlight RECK as a potential target for therapeutic development.
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