{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T02:02:40Z","timestamp":1783821760745,"version":"3.55.0"},"reference-count":94,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The New Jersey Commission on Brain Injury Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cognitive disorders and psychiatric pathologies, particularly Alzheimer\u2019s disease (AD) and Major depressive disorder (MDD), represent a considerable health burden, impacting millions of people in the United States and worldwide. Notably, comorbidities of MDD and anxiety are prevalent in the early stages of mild cognitive impairment (MCI), which is the preceding phase of Alzheimer\u2019s disease and related dementia (ADRD). The symptoms of MDD and anxiety affect up to 80% of individuals in the advanced stages of the neurodegenerative conditions. Despite overlapping clinical manifestations, the pathogenesis of AD\/ADRD and MDD remains inadequately elucidated. Until now, dozens of drugs for treating AD\/ADRD have failed in clinical trials because they have not proven beneficial in reversing or preventing the progression of these neuropsychiatric indications. This underscores the need to identify new drug targets that could reverse neuropsychiatric symptoms and delay the progress of AD\/ADRD. In this context, phosphodiesterase 4 (PDE4) arises as a primary enzyme in the modulation of cognition and mood disorders, particularly through its enzymatic action on cyclic adenosine monophosphate (cAMP) and its downstream anti-inflammatory pathways. Despite the considerable cognitive and antidepressant potential of PDE4 inhibitors, their translation into clinical practice is hampered by profound side effects. Recent studies have focused on the effects of PDE4 and its subtype-selective isoform inhibitors, aiming to delineate their precise mechanistic contributions to neuropsychiatric symptoms with greater specificity. This review aims to analyze the current advances regarding PDE4 inhibition\u2014specifically the selective targeting of its isoforms and elucidate the therapeutic implications of enhanced cAMP signaling and the consequent anti-inflammatory responses in ameliorating the symptomatology associated with AD and ADRD.<\/jats:p>","DOI":"10.3390\/cells14030164","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T03:40:17Z","timestamp":1737517217000},"page":"164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Phosphodiesterase 4 Inhibition in Neuropsychiatric Disorders Associated with Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Jiming","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyao","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Nursing and Rehabilitation, Nantong University, Nantong 226007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baomin","family":"Dou","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhutao","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2021). 2021 Alzheimer\u2019s disease facts and figures. 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