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Dipeptidyl Peptidase 4 Mediated Caspase-8 Affects Cognitive Impairment in Mice With Alzheimer's Disease
XinYi Wang1,2, Li Chen3, JiaYao Qiu1,4
1Department of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing, China.
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 Aβ25-35 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 Aβ25-35 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.
Insights
Dipeptidyl peptidase 4 (DPP4) knockout improved cognitive function in Alzheimer's disease (AD) mice. This suggests DPP4 inhibition may be a therapeutic strategy for AD by modulating pyroptosis and apoptosis pathways.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment.
- Dipeptidyl peptidase 4 (DPP4) is implicated in various biological processes, but its role in AD pathogenesis is unclear.
Purpose of the Study:
- To investigate the effect of dipeptidyl peptidase 4 (DPP4) on cognitive impairment in an Alzheimer's disease (AD) mouse model.
- To explore the underlying molecular mechanisms involving pyroptosis and apoptosis pathways.
Main Methods:
- Utilized a mouse model of AD induced by Aβ25-35 microinjection.
- Administered DPP4 knockout and sitagliptin (DPP4 inhibitor) treatments.
- Assessed cognitive function using the Morris water maze test.
- Analyzed protein expression levels in the hippocampus via Western blot.
Main Results:
- DPP4 knockout significantly improved spatial learning and memory in AD mice.
- DPP4 knockout upregulated BDNF, CREB, and Bcl-2, while downregulating Caspase-8, NLRP3, Caspase-1, GSDMD, IL-1β, Caspase-3, and Bax.
- Sitagliptin treatment in vitro mimicked these protective effects.
- Caspase-8 inhibition affected pyroptosis markers but showed no additive effect with sitagliptin.
Conclusions:
- DPP4 knockout ameliorates cognitive dysfunction in AD mice.
- The protective effects are mediated by the regulation of pyroptosis and apoptosis pathways, potentially involving Caspase-8.
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