{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:02:50Z","timestamp":1792206170580,"version":"4.4.0"},"reference-count":27,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T00:00:00Z","timestamp":1671148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Inositol polyphosphate\u20105\u2010phosphatase (INPP5D)<\/jats:italic> is a microglia\u2010enriched lipid phosphatase in the central nervous system. A non\u2010coding variant (rs35349669) in <jats:italic>INPP5D<\/jats:italic> increases the risk for Alzheimer's disease (AD), and elevated INPP5D expression is associated with increased plaque deposition. INPP5D negatively regulates signaling via several microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2); however, the impact of <jats:italic>INPP5D<\/jats:italic> inhibition on AD pathology remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used the 5xFAD mouse model of amyloidosis to assess how <jats:italic>Inpp5d<\/jats:italic> haplodeficiency regulates amyloid pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Inpp5d<\/jats:italic> haplodeficiency perturbs the microglial intracellular signaling pathways regulating the immune response, including phagocytosis and clearing of amyloid beta (A\u03b2). It is important to note that <jats:italic>Inpp5d<\/jats:italic> haploinsufficiency leads to the preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by <jats:italic>Inpp5d<\/jats:italic> haploinsufficiency are related to synaptic regulation and immune cell activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data demonstrate that <jats:italic>Inpp5d<\/jats:italic> haplodeficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D is a potential therapeutic strategy for AD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.12849","type":"journal-article","created":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T07:00:34Z","timestamp":1671174034000},"page":"2528-2537","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["<i>INPP5D<\/i> deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease"],"prefix":"10.1002","volume":"19","author":[{"given":"Peter Bor\u2010Chian","family":"Lin","sequence":"first","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy Po\u2010Yi","family":"Tsai","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disha","family":"Soni","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Lee\u2010Gosselin","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Moutinho","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Anatomy Cell Biology &amp; Physiology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shweta S.","family":"Puntambekar","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary E.","family":"Landreth","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Anatomy Cell Biology &amp; Physiology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce T.","family":"Lamb","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian L.","family":"Oblak","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Radiology and Imaging Sciences Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702\u2010010\u20100433\u20104"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp406"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2147\/CIA.S105769"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2014.05.006"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2802"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264\u2010016\u20100011\u20103"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12648"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105303"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD\u2010161211"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000500"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2020.12.035"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010017\u20100197\u20105"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471\u20104159.2009.06042.x"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.238030"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abl7634"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.713726"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2013.09.016"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2016.01.001"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD\u2010143120"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.05.027"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0169\u2010328x(98)00040\u20100"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21020678"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2019.06.003"},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","unstructured":"CastranioEL HaselP Haure\u2010MirandeJ\u2010V et\u00a0al.INPP5D limits plaque formation and glial reactivity in the APP\/PS1 mouse model of Alzheimer's disease.bioRxiv.2022. doi:10.1101\/2022.04.29.490076","DOI":"10.1101\/2022.04.29.490076"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.3844721"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102007\u201002\u2010073874"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.018"}],"container-title":["Alzheimer's &amp; 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