DSS-induced colitis exacerbates Alzheimer's pathology via neutrophil elastase and cathepsin B activation

Abstract

Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid plaques and neuroinflammation, which collectively result in cognitive decline. Peripheral inflammation, particularly intestinal inflammation, has been implicated in exacerbating AD pathology via the gut-brain axis. This study investigated the effects of dextran sulfate sodium (DSS)-induced colitis on amyloid-beta (Aβ) pathology, synaptic integrity, and cognitive function in 5xFAD mice, and explored the roles of neutrophil elastase (NE) and Cathepsin B in these processes. DSS-induced colitis significantly worsened Aβ pathology, evidenced by increased Aβ plaque deposition and elevated soluble Aβ_1-42 levels in the brain of 5xFAD mice. The inflammatory state triggered extensive neutrophil infiltration and elevated NE levels in the hippocampus, which were closely associated with Cathepsin B activation. This enzymatic cascade is associated with synaptic damage and cognitive deficits. Treatment with the NE inhibitor Sivelestat effectively suppressed NE-mediated Cathepsin B activation, reduced Aβ pathology, restored dendritic spine density, and improved cognitive performance. Additionally, the Cathepsin B inhibitor CA-074 methyl ester (CA-074Me) mitigated the adverse effects of DSS-induced colitis, further emphasizing the role of Cathepsin B in mediating inflammation-driven AD pathology. These findings reveal that the NE-Cathepsin B axis links peripheral inflammation to exacerbated Aβ pathology, synaptic damage, and cognitive impairment, underscoring the potential of targeting NE and Cathepsin B as therapeutic strategies for inflammation-driven AD progression.

Keywords: Alzheimer's disease; Cathepsin B; gut-brain axis; neuroinflammation; neutrophil elastase.