{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:07:17Z","timestamp":1789578437143,"version":"build-2803163510"},"reference-count":31,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009888","name":"Tuscany Region","doi-asserted-by":"publisher","award":["Health Research Call 2018 DSB. AD006.289\u2014NEWDEM"],"award-info":[{"award-number":["Health Research Call 2018 DSB. AD006.289\u2014NEWDEM"]}],"id":[{"id":"10.13039\/501100009888","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thriving literature underlines white blood cell involvement in the inflammatory processes of Alzheimer\u2019s Disease (AD). Among leukocytes, lymphocytes have been considered sentinels of neuroinflammation for years, but recent findings highlighted the pivotal role of neutrophils. Since neutrophils that infiltrate the brain through the brain vascular vessels may affect the immune function of microglia in the brain, a close investigation of the interaction between these cells is important in understanding neuroinflammatory phenomena and the immunological aftermaths that follow. This study aimed to observe how peripheral leukocyte features change at different stages of AD to identify potential molecular markers when the first features of pathological neurodegeneration arise. For this purpose, the examined patients were divided into Mild Cognitive Impairment (MCI) and severely impaired patients (DAT) based on their Cognitive Dementia Rating (CDR). The evaluation of the neutrophil-to-lymphocytes ratio and the morphology and function of leukocytes showed a close relationship between the ultrastructural and the molecular features in AD progression and suggested putative markers for the early stages of the disease.<\/jats:p>","DOI":"10.3390\/ijms24097909","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T02:50:00Z","timestamp":1682563800000},"page":"7909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Ultrastructural and Molecular Investigation on Peripheral Leukocytes in Alzheimer\u2019s Disease Patients"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0986-6500","authenticated-orcid":false,"given":"Roberta","family":"Giannelli","sequence":"first","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Canale","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy"},{"name":"Department of Experimental and Clinical Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7504-0379","authenticated-orcid":false,"given":"Renata","family":"Del Carratore","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6492-6038","authenticated-orcid":false,"given":"Alessandra","family":"Falleni","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2650-1834","authenticated-orcid":false,"given":"Margherita","family":"Bernardeschi","sequence":"additional","affiliation":[{"name":"Italian Institute of Technology, Center for Materials Interfaces, Smart Bio-Interfaces, 56025 Pontedera, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4249-6775","authenticated-orcid":false,"given":"Francesca","family":"Forini","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Biagi","sequence":"additional","affiliation":[{"name":"BMS Multispecialistic Biobank-Biobank Unit, AOUP\u2014Pisa University Hospital, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0784-302X","authenticated-orcid":false,"given":"Olivia","family":"Curzio","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0767-1558","authenticated-orcid":false,"given":"Paolo","family":"Bongioanni","sequence":"additional","affiliation":[{"name":"Severe Acquired Brain Injuries Dpt Section, Azienda Ospedaliero Universitaria Pisana, 56100 Pisa, Italy"},{"name":"NeuroCare Onlus, 56100 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/s41423-021-00832-3","article-title":"Neutrophils in chronic inflammatory diseases","volume":"19","author":"Soehnlein","year":"2022","journal-title":"Cell Mol. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"988481","DOI":"10.3389\/fimmu.2022.988481","article-title":"Excessive intake of sugar: An accomplice of inflammation","volume":"13","author":"Ma","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.3389\/fimmu.2020.01823","article-title":"Psychological stress, intestinal barrier dysfunctions, and autoimmune disorders: An overview","volume":"11","author":"Menard","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/s41423-019-0223-3","article-title":"The benefits of neuroinflammation for the repair of the injured central nervous system","volume":"16","author":"Yong","year":"2019","journal-title":"Cell Mol. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/imm.12922","article-title":"Inflammation in CNS neurodegenerative diseases","volume":"154","author":"Stephenson","year":"2018","journal-title":"Immunology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.neuron.2020.06.002","article-title":"The bidirectional relationship of depression and inflammation: Double trouble","volume":"107","author":"Beurel","year":"2020","journal-title":"Neuron"},{"key":"ref_7","first-page":"4626540","article-title":"Lymphocytes and inflammatory mediators in the interplay between brain and blood in Alzheimer\u2019s Disease: Potential pools of new biomarkers","volume":"2017","author":"Wojda","year":"2017","journal-title":"J. Immunol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"104580","DOI":"10.1016\/j.phrs.2019.104580","article-title":"The role of neutrophils in neuro-immune modulation","volume":"151","author":"Kanashiro","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4579","DOI":"10.1126\/sciimmunol.aat4579","article-title":"Neutrophils: New insights and open questions","volume":"3","author":"Ley","year":"2018","journal-title":"Sci. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Van Haastert, P.J.M. (2020). Unified control of amoeboid pseudopod extension in multiple organisms by branched F-actin in the front and parallel F-actin\/myosin in the cortex. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0243442"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1172\/JCI124616","article-title":"More friend than foe: The emerging role of neutrophils in tissue repair","volume":"129","author":"Peiseler","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"836754","DOI":"10.3389\/fimmu.2022.836754","article-title":"Metabolic Reprogramming mediates delayed apoptosis of human neutrophils infected with Francisella tularensis","volume":"13","author":"Krysa","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/cei.13525","article-title":"Type I interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression","volume":"203","author":"Moots","year":"2021","journal-title":"Clin. Exp. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"577398","DOI":"10.1016\/j.jneuroim.2020.577398","article-title":"The neutrophil-to-lymphocyte ratio in Alzheimer\u2019s Disease: Current understanding and potential applications","volume":"349","author":"Sayed","year":"2020","journal-title":"J. Neuroimmunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"613733","DOI":"10.3389\/fcell.2020.613733","article-title":"Neutrophils return to bloodstream through the brain blood vessel after crosstalk with microglia during LPS-induced neuroinflammation","volume":"8","author":"Kim","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9641","DOI":"10.1007\/s11033-022-07873-5","article-title":"The impact of Nrf2\/HO-1, caspase-3\/Bax\/Bcl2 and ATF6\/IRE1\/PERK\/GRP78 signaling pathways in the ameliorative effects of morin against methotrexate-induced testicular toxicity in rats","volume":"49","author":"Caglayan","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1126\/science.1059108","article-title":"Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death","volume":"292","author":"Wei","year":"2001","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"888946","DOI":"10.3389\/fnagi.2022.888946","article-title":"Association of peripheral blood cell profile with Alzheimer\u2019s disease: A meta-analysis","volume":"14","author":"Huang","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"773984","DOI":"10.3389\/fnagi.2021.773984","article-title":"The neutrophil to lymphocyte ratio is associated with the risk of subsequent dementia in the framingham heart study","volume":"13","author":"Johnson","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.3389\/fimmu.2019.02231","article-title":"Mimicry of central-peripheral immunity in Alzheimer\u2019s disease and discovery of neurodegenerative roles in neutrophil","volume":"10","author":"Park","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"106678","DOI":"10.1016\/j.intimp.2020.106678","article-title":"Microglia-released leukotriene B4 promotes neutrophil infiltration and microglial activation following intracerebral hemorrhage","volume":"85","author":"Hijioka","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e200023","DOI":"10.1212\/NXI.0000000000200023","article-title":"Microglia as central protagonists in the chronic stress response","volume":"9","author":"Schramm","year":"2022","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2902","DOI":"10.1007\/s12035-020-01929-y","article-title":"Molecular mechanisms of ER stress and UPR in the pathogenesis of Alzheimer\u2019s disease","volume":"57","author":"Uddin","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_24","first-page":"6483","article-title":"High Expression of active ATF6 aggravates endoplasmic reticulum stress-induced vascular endothelial cell apoptosis through the mitochondrial apoptotic pathway","volume":"17","author":"Huang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Merighi, A., and Lossi, L. (2022). Endoplasmic reticulum stress signaling and neuronal cell death. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315186"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.3389\/fimmu.2018.03083","article-title":"The C\/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection","volume":"9","author":"Hu","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1096\/fba.2020-00138","article-title":"Leidal and Jayanta Debnath Emerging roles for the autophagy machinery in extracellular vesicle biogenesis and secretion","volume":"3","author":"Andrew","year":"2021","journal-title":"FASEB Bioadv."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Trifylli, E.M., Kriebardis, A.G., Koustas, E., Papadopoulos, N., Deutsch, M., Aloizos, G., Fortis, S.P., Papageorgiou, E.G., Tsagarakis, A., and Manolakopoulos, S. (2022). The emerging role of extracellular vesicles and autophagy machinery in NASH\u2014Future horizons in NASH management. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012185"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Baldini, A., Greco, A., Lomi, M., Giannelli, R., Canale, P., Diana, A., Dolciotti, C., Del Carratore, R., and Bongioanni, P. (2022). Blood Analytes as biomarkers of mechanisms involved in Alzheimer\u2019s disease progression. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113289"},{"key":"ref_30","first-page":"194","article-title":"A subcellular analysis of genetic modulation of PINK1 on mitochondrial alterations, autophagy and cell death","volume":"150","author":"Lenzi","year":"2012","journal-title":"Arch. Ital. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/s41419-018-1080-1","article-title":"Activation of the interferon type I response rather than autophagy contributes to myogenesis inhibition in congenital DM1 myoblasts","volume":"9","author":"Rizzo","year":"2018","journal-title":"Cell Death Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/7909\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:23:51Z","timestamp":1760124231000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/7909"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,26]]},"references-count":31,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24097909"],"URL":"https:\/\/doi.org\/10.3390\/ijms24097909","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,26]]}}}