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Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOAD. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A (PKA) activation and cAMP response element-binding protein phosphorylation. In addition, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP\/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.<\/jats:p>","DOI":"10.1093\/hmg\/ddab090","type":"journal-article","created":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T07:08:09Z","timestamp":1617779289000},"page":"811-822","source":"Crossref","is-referenced-by-count":21,"title":["Exome sequencing revealed\n                    <i>PDE11A<\/i>\n                    as a novel candidate gene for early-onset Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"30","author":[{"given":"Wei","family":"Qin","sequence":"first","affiliation":[{"name":"Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aihong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumei","family":"Zuo","sequence":"additional","affiliation":[{"name":"Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longfei","family":"Jia","sequence":"additional","affiliation":[{"name":"Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyu","family":"Li","sequence":"additional","affiliation":[{"name":"Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiping","family":"Wei","sequence":"additional","affiliation":[{"name":"Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Jin","sequence":"additional","affiliation":[{"name":"Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University, St. Louis, MO 63110, USA"},{"name":"NeuroGenomics and Informatics Center, Washington University, St. Louis, MO 63110, USA"},{"name":"Department of Genetics, Washington University, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno A","family":"Benitez","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University, St. Louis, MO 63110, USA"},{"name":"NeuroGenomics and Informatics Center, Washington University, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Jia","sequence":"additional","affiliation":[{"name":"Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China"},{"name":"Beijing Key Laboratory of Geriatric Cognitive Disorders, Capital Medical University, Beijing 10053, China"},{"name":"Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing 10053, China"},{"name":"Center of Alzheimer\u2019s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 10053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"2021070819095800400_ref1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S1474-4422(18)30403-4","article-title":"Global, regional, and national burden of Alzheimer\u2019s disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"GBD Dementia Collaborators","year":"2019","journal-title":"Lancet Neurol."},{"key":"2021070819095800400_ref2","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.jalz.2007.04.381","article-title":"Forecasting the global burden of Alzheimer\u2019s disease","volume":"3","author":"Brookmeyer","year":"2007","journal-title":"Alzheimers 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