GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein
Year: 2021
Type: article
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.
Source: Science Translational Medicine
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: American Federation for Aging Research, American Foundation for Aging Research, Johns Hopkins University, Kanazawa University, National Institutes of Health, Alzheimer's Disease Research Center, Emory University, Center for Neuroscience Research, Japan Society for the Promotion of Science, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: G1292682725, GDE2: Roles in neuronal survival and degeneration, Research Center Without Walls for Huntington's Disease, JHU Center for Neuroscience Research, Mechanisms of amyloid precursor protein processing: novel regulation of α-secretase activity, G7252923192, RB1 tumor suppressor functions in metabolism, G7712181638, G7868420312, G7935835019, G8121226415, Cellular and Molecular Medicine, Johns Hopkins Alzheimer's Disease Research Center, Research Training in Age-Related Cognitive Disorders
OpenAlex ID: W3138745382