{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T19:20:17Z","timestamp":1793388017350,"version":"4.5.0"},"reference-count":75,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp; Dementia"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Impaired insulin (INS) and insulin\u2010like growth factor 1 (IGF\u20101) signaling are features of both brain aging and late\u2010onset Alzheimer's disease (LOAD). However, their exact underlying mechanisms and cause\u2010and\u2010effect linkages, including the downstream regulation of endocytosis and autophagy, are still not well understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We investigated INS\/IGF\u20101 signaling and its connection with endocytic and autophagic processes in fibroblasts from LOAD patients and healthy young or old control individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Compared to control old\u2010age cells, protein levels in the INS\/IGF\u20101 signaling cascade were elevated in LOAD cells, but activation of AKT was reduced. The activation of the INS\/IGF\u20101\/AKT\/FOXO1 or mTOR axes and associated endo\u2010 and autophagic processes were largely intact in old\u2010age but disrupted in LOAD fibroblasts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our results suggest that reduced AKT activation, in the context of altered INS\/IGF\u20101 signaling, and connected alterations of endocytosis and autophagy are features of LOAD pathology but not aging, per se.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Levels of insulin\/insulin\u2010like growth factor 1 (INS\/IGF\u20101) factors in late\u2010onset Alzheimer's disease (LOAD) cells are higher than in healthy old controls.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>AKT activation by INS\/IGF\u20101 signaling is specifically diminished in LOAD cells.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>INS\/IGF\u20101\/AKT\/forkhead box protein O1\/mechanistic target of rapamycin kinase related endocytosis\/autophagy are disrupted in LOAD cells.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Intracellular endocytic\/autophagic structure distribution is altered in LOAD cells.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>INS\/IGF\u20101 reverses endocytic\/autophagic processes in LOAD versus old control cells.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70099","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T05:02:41Z","timestamp":1751605361000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Interconnections of insulin\/IGF\u20101 signaling and autophagy abnormalities in Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Wang","family":"Liao","sequence":"first","affiliation":[{"name":"Department of Neurology The Second Affiliated Hospital Guangzhou Medical University  Guangzhou China"},{"name":"Department of Psychiatry McLean Hospital Harvard Medical School  Belmont Massachusetts USA"},{"name":"Basic Neuroscience Division McLean Hospital Harvard Medical School  Belmont Massachusetts USA"},{"name":"Program for Neuropsychiatric Research McLean Hospital Harvard 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