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Dipeptidyl Peptidase 4 Mediated Caspase‐8 Affects Cognitive Impairment in Mice With Alzheimer's Disease

Year: 2025

Type: article

Abstract: ABSTRACT To investigate the effect of dipeptidyl peptidase 4 (DPP4) on cognitive impairment in Alzheimer's disease (AD), the present study used seven‐week‐old male C57BL/6J and DPP4 knockout mice. The AD model was induced by microinjection of Aβ 25‐35 into the lateral ventricle. Morris water maze test showed that DPP4 knockout significantly improved the spatial learning and memory abilities of AD mice. Western blot results showed that DPP4 knockout increased the expression levels of BDNF, CREB and Bcl‐2 in the hippocampus of AD mice while the expression levels of Caspase‐8, pyroptosis‐related proteins NLRP3, Caspase‐1, GSDMD, IL‐118, IL‐1β, and apoptosis‐related proteins Caspase‐3 and Bax were decreased. Similar results were observed after HT22 neurons were treated with Aβ 25‐35 and the DPP4 inhibitor sitagliptin (Sit). Moreover, the treatment with a Caspase‐8 inhibitor (Z‐LETD‐FMK) showed that the inhibition of Caspase‐8 inhibited the expression of NLRP3 and Caspase‐1 in the AD model cells, but had no further inhibitory effect under the treatment of Sit. Our results suggest that DPP4 knockout may ameliorate learning and memory dysfunction in AD model mice by regulating pyroptosis and apoptosis pathways through Caspase‐8.

Source: The FASEB Journal

DOI: 10.1096/fj.202501322rr