Key result
A CCK analogue significantly alleviated cognitive deficits, reduced Aβ1-42 expression, and regulated mitochondrial dynamics via the AMPK/Drp1 pathway in APP/PS1 Alzheimer's disease mice.
Why the study?
No drugs currently reverse or slow Alzheimer's disease progression, and the mechanisms underlying the neuroprotective effects of the protease-resistant cholecystokinin analogue CCK-8L remained to be elucidated.
Does a CCK analogue improve cognitive deficits and regulate mitochondrial dynamics in APP/PS1 Alzheimer's disease mice?
Does a CCK analogue improve cognitive deficits and regulate mitochondrial dynamics in APP/PS1 Alzheimer's disease mice?
Answers are grounded in this paper and cite their sources.
A CCK analogue demonstrates neuroprotective effects in an Alzheimer's disease mouse model by improving cognitive function and regulating mitochondrial dynamics via the AMPK/Drp1 pathway.
BACKGROUND: There are no drugs on the market that can reverse or slow Alzheimer's disease (AD) progression. A protease-resistant Cholecystokinin (CCK) analogue used in this study is based on the basic structure of CCK, which further increases the stability of the peptide fragment and prolongs its half-life in vivo. We observed a neuroprotective effect of CCK-8L in APPswe/PS1dE9 (APP/PS1) AD mice. However, its corresponding mechanisms still need to be elucidated. OBJECTIVE: This study examined CCK-8L's neuroprotective effects in enhancing cognitive impairment by regulating mitochondrial dynamics through AMPK/Drp1 pathway in the APP/PS1 AD mice. METHODS: Behavioural tests are applied to assess competence in cognitive functions. Transmission electron microscopy (TEM) was performed to observe the ultrastructure of mitochondria of hippocampal neurons, Immunofluorescent staining was employed to assay for Aβ1-42, APP, Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and dynamin-related protein1 (Drp1). CRISPR/Cas9 was utilized for targeted knockout of the CCKB receptor (CCKBR) in the mouse APP/PS1 hippocampal CA1 region. A model of lentiviral vector-mediated overexpression of APP in N2a cells was constructed. RESULTS: In vivo, experiments revealed that CCK analogue and liraglutide significantly alleviated cognitive deficits in APP/PS1 mice, reduced Aβ1-42 expression, and ameliorated l damage, which is associated with CCKBR activation in the hippocampal CA1 region of mice. In vitro tests showed that CCK inhibited mitochondrial fission and promoted fusion through AMPK/Drp1 pathway. CONCLUSIONS: CCK analogue ameliorates cognitive deficits and regulates mitochondrial dynamics by activating the CCKB receptor and the AMPK/Drp1 pathway in AD mice.
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Li et al. (2024) studied Alzheimer's disease (APP/PS1 mice). CCK analogue (CCK-8L) was evaluated on Cognitive deficits, Aβ1-42 expression, and mitochondrial dynamics. A CCK analogue significantly alleviated cognitive deficits, reduced Aβ1-42 expression, and regulated mitochondrial dynamics via the AMPK/Drp1 pathway in APP/PS1 Alzheimer's disease mice.
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