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The detailed mechanisms by which protein kinase C-delta (PKC\u03b4) contributes to A\u03b2 toxicity is not yet entirely understood. Using fully differentiated primary rat cortical neurons, we found that inhibition of A\u03b225-35-induced PKC\u03b4 increased cell viability with restoration of neuronal morphology. Using cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) as the respective markers for the G1-, S-, and G2\/M-phases, PKC\u03b4 inhibition mitigated cell cycle reentry (CCR) and subsequent caspase-3 cleavage induced by both A\u03b225-35 and A\u03b21-42 in the post-mitotic cortical neurons. Upstream of PKC\u03b4, signal transducers and activators of transcription (STAT)-3 mediated PKC\u03b4 induction, CCR, and caspase-3 cleavage upon A\u03b2 exposure. Downstream of PKC\u03b4, aberrant neuronal CCR was triggered by overactivating cyclin-dependent kinase-5 (CDK5) via calpain2-dependent p35 cleavage into p25. Finally, PKC\u03b4 and CDK5 also contributed to A\u03b225-35 induction of p53-upregulated modulator of apoptosis (PUMA) in cortical neurons. Together, we demonstrated that, in the post-mitotic neurons exposed to A\u03b2s, STAT3-dependent PKC\u03b4 expression triggers calpain2-mediated p35 cleavage into p25 to overactivate CDK5, thus leading to aberrant CCR, PUMA induction, caspase-3 cleavage, and ultimately apoptosis.<\/jats:p>","DOI":"10.3390\/ijms25179626","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T06:44:29Z","timestamp":1725518669000},"page":"9626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Protein Kinase C-Delta Mediates Cell Cycle Reentry and Apoptosis Induced by Amyloid-Beta Peptide in Post-Mitotic Cortical Neurons"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0981-1335","authenticated-orcid":false,"given":"Ming-Hsuan","family":"Wu","sequence":"first","affiliation":[{"name":"Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1230-9622","authenticated-orcid":false,"given":"A-Ching","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan"},{"name":"Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan"},{"name":"Department of Sports Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Heng","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"Lien","sequence":"additional","affiliation":[{"name":"Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chun","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Taipei City Hospital Renai Branch, Taipei 106243, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5544-7561","authenticated-orcid":false,"given":"Ding-I","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"},{"name":"Brain Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer disease","volume":"7","author":"Knopman","year":"2021","journal-title":"Nat. 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