Secretory form of viral protease NIa ameliorates amyloid-β pathology and cognitive deficits in a mouse model of Alzheimer’s disease

Alzheimer’s disease (AD), the leading cause of dementia, is characterized by extracellular amyloid-β (Aβ) accumulation. Immunotherapies targeting Aβ clearance show promise, highlighting the therapeutic value of enhancing Aβ removal. We previously identified that nuclear inclusion a (NIa), a plant viral protease, fortuitously cleaves Aβ with strict sequence specificity. Here, we engineered a secretory form, SecNIa, to degrade extracellular Aβ. SecNIa was efficiently secreted from transfected cells while retaining potent Aβ-cleaving activity. Adeno-associated virus (AAV)-mediated delivery of SecNIa into 5xFAD mice resulted in robust hippocampal expression and cerebrospinal fluid secretion. SecNIa expression significantly reduced soluble and insoluble Aβ, decreased hippocampal plaques, and improved cognition, fully normalizing recognition memory and enhancing spatial learning. These findings establish SecNIa as a promising therapeutic strategy to directly target pathogenic extracellular Aβ in AD.