TY - JOUR
T1 - GDE2-RECK controls ADAM10 α-secretase-mediated cleavage of amyloid precursor protein
AU - Nakamura, Mai
AU - Li, Yuhan
AU - Choi, Bo Ran
AU - Matas-Rico, Elisa
AU - Troncoso, Juan
AU - Takahashi, Chiaki
AU - Sockanathan, Shanthini
N1 - Funding Information:
This work was funded by the following: 5T32GM08752 (NIH) to M.N., 90068104 (AFAR) to M.N., F31AG056088 (NIH) to M.N., Johns Hopkins ADRC Pilot Project Award to S.S., Johns Hopkins Innovation Award to S.S., Johns Hopkins President's Frontier Finalist Award to S.S., RO1AG062671 (NIH) to S.S., and the JHU Alzheimer's Research Center NIA P30AG066507 for support of J.T.
Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved.
PY - 2021/3/17
Y1 - 2021/3/17
N2 - 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-RECKADAM10 pathway in AD pathophysiology and highlight RECK as a potential target for therapeutic development.
AB - 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-RECKADAM10 pathway in AD pathophysiology and highlight RECK as a potential target for therapeutic development.
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U2 - 10.1126/scitranslmed.abe6178
DO - 10.1126/scitranslmed.abe6178
M3 - Article
C2 - 33731436
AN - SCOPUS:85103058796
SN - 1946-6234
VL - 13
JO - Science translational medicine
JF - Science translational medicine
IS - 585
M1 - eabe6178
ER -