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Excess reactive oxygen species (ROS) are a major contributor to oxidative stress. As vital sources of ROS, mitochondria are also the primary targets of ROS attack. Seeking effective avenues to reduce oxidative stress has attracted increasing attention for AD intervention.<\/jats:p><\/jats:sec>Methods<\/jats:title>We developed liposome\u2010packaged Ligustilide (LIG) and investigated its effects on mitochondrial function and AD\u2010like pathology in the APPswe\/PS1dE9 (APP\/PS1) mouse model of AD, and analyzed possible mechanisms.<\/jats:p><\/jats:sec>Results<\/jats:title>We observed that LIG\u2010loaded liposome (LIG\u2010LPs) treatment reduced oxidative stress and \u03b2\u2010amyloid (A\u03b2) deposition and mitigated cognitive impairment in APP\/PS1 mice. LIG management alleviated the destruction of the inner structure in the hippocampal mitochondria and ameliorated the imbalance between mitochondrial fission and fusion in the APP\/PS1 mouse brain. We showed that the decline in cAMP\u2010dependent protein kinase A (PKA) and A\u2010kinase anchor protein 1 for PKA (AKAP1) was associated with oxidative stress and AD\u2010like pathology. We confirmed that LIG\u2010mediated antioxidant properties and neuroprotection were involved in upregulating the PKA\/AKAP1 signaling in APPswe cells in vitro.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Liposome packaging for LIG is relatively biosafe and can overcome the instability of LIG. LIG alleviates mitochondrial dysfunctions and cognitive impairment via the PKA\/AKAP1 signaling pathway. Our results provide experimental evidence that LIG\u2010LPs may be a promising agent for AD therapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14460","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T05:20:28Z","timestamp":1695014428000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Ligustilide\u2010loaded liposome ameliorates mitochondrial impairments and improves cognitive function via the PKA<\/scp>\/AKAP1<\/scp> signaling pathway in a mouse model of Alzheimer's disease"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4746-3542","authenticated-orcid":false,"given":"Qi","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Health Sciences Institute of China Medical University Shenyang China"},{"name":"Key Laboratory of Medical Cell Biology of Ministry 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