Delta-secretase, a lysosomal asparagine endopeptidase (AEP), simultaneously cleaves both APP and tau, controlling the onset of pathogenesis of Alzheimer’s disease (AD). However, how this protease is post-translationally regulated remains unclear. Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. Delta-secretase is highly phosphorylated in human AD brains, tightly correlated with SRPK2 activity. Overexpression of a phosphorylation mimetic (S226D) in young 3xTg mice strongly promotes APP and tau fragmentation and facilitates amyloid plaque deposits and neurofibrillary tangle (NFT) formation, resulting in cognitive impairment. Conversely, viral injection of the non-phosphorylatable mutant (S226A) into 5XFAD mice decreases APP and tau proteolytic cleavage, attenuates AD pathologies, and reverses cognitive defects. Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis.

δ-分泌酶，一种溶酶体天冬酰胺内肽酶（AEP），同时裂解APP和tau，控制了阿尔茨海默氏病（AD）的发病机理。但是，尚不清楚该蛋白酶在翻译后的调控方式。在这里我们报告丝氨酸精氨酸蛋白激酶2（SRPK2）磷酸化δ分泌酶，并增强其酶促活性。SRPK2使δ-分泌酶上的丝氨酸226磷酸化并加速其自催化裂解，从而导致其胞质易位和酶活性升高。δ-分泌酶在人类AD大脑中高度磷酸化，与SRPK2活性紧密相关。在年轻的3xTg小鼠中磷酸化模拟物（S226D）的过度表达强烈促进APP和tau片段化，并促进淀粉样斑块沉积和神经原纤维缠结（NFT）的形成，导致认知障碍。相反，将病毒的非磷酸化突变体（S226A）病毒注射到5XFAD小鼠中会减少APP和tau蛋白水解裂解，减弱AD病理，并逆转认知缺陷。我们的发现支持SRPK2引起的δ分泌酶磷酸化在加重AD发病机理中起关键作用。