{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T02:29:28Z","timestamp":1780453768893,"version":"3.54.1"},"posted":{"date-parts":[[2024,9,19]]},"group-title":"Neuroscience","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Ample studies attribute cognitive decline in Alzheimer\u2019s disease to amyloid-\u03b2 deposition\n                  <jats:sup>1\u20136<\/jats:sup>\n                  . However, brain amyloid-\u03b2 accumulation that saturates years before the manifestation of clinical symptoms is dissociated with cognitive decline of the disease\n                  <jats:sup>7<\/jats:sup>\n                  . It is unknown how these two processes are mechanistically linked. In this and our accompanied study, we report that thiamine pyrophosphokinase-1 (TPK) deficiency plays essential roles in both processes via distinct mechanisms. Here we describe that diminished microglia Tpk controls the propagation of amyloid-\u03b2 plaques. In APP\/PS1 transgenic mice, microglia showed elevated\n                  <jats:italic>Tpk<\/jats:italic>\n                  expression at 2-month-old, but reduction in a plaque-centric manner at 8-month-old. Interestingly, lipopolysaccharide, but not amyloid-\u03b2, induceed\n                  <jats:italic>Tpk<\/jats:italic>\n                  reduction in cultured microglia.\n                  <jats:italic>Tpk<\/jats:italic>\n                  reduction led to microglia dysfunction, showing volatile motility but reduced phagocytosis and weak response to focal tissue injury, with accumulation of intracellular lipid droplets and abnormal mitochrondria. In Alzheimer\u2019s disease mice, microglia-specific knockout of\n                  <jats:italic>Tpk<\/jats:italic>\n                  caused diminished plaque coverage, exacerbated plaque burden and synaptic loss. However, increased plaques were not accompanied by the development of neurofibrillary tangles or brain atrophy, in contrast to the phenotype described in our accompanied paper with neuronal\n                  <jats:italic>Tpk<\/jats:italic>\n                  deletion. In conclusion, plaque-induced inflammation reduces\n                  <jats:italic>Tpk<\/jats:italic>\n                  in microglia, selectively exacerbating the spread of amyloid pathology.\n                <\/jats:p>","DOI":"10.1101\/2024.09.18.613405","type":"posted-content","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T07:08:47Z","timestamp":1726729727000},"source":"Crossref","is-referenced-by-count":2,"title":["The mechanism and consequences of amyloid-\u03b2 modulating thiamine pyrophosphokinase-1 expression in microglia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4616-7562","authenticated-orcid":false,"given":"Xiaoqin","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8607-063X","authenticated-orcid":false,"given":"Ruoqi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7252-7854","authenticated-orcid":false,"given":"Hongyan","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7423-3729","authenticated-orcid":false,"given":"Peiwen","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanwen","family":"Kou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9803-6930","authenticated-orcid":false,"given":"Shaoming","family":"Sang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6545-6680","authenticated-orcid":false,"given":"Yingfeng","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0313-7498","authenticated-orcid":false,"given":"Wenwen","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0278-2371","authenticated-orcid":false,"given":"Boru","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2019-6472","authenticated-orcid":false,"given":"Qiang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3346-1463","authenticated-orcid":false,"given":"Peng","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-3441","authenticated-orcid":false,"given":"Chunjiu","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024092301101140000_2024.09.18.613405v1.1","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: the amyloid cascade hypothesis","volume":"256","year":"1992","journal-title":"Science (New York, N.Y.)"},{"key":"2024092301101140000_2024.09.18.613405v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/349704a0"},{"key":"2024092301101140000_2024.09.18.613405v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/376775a0"},{"key":"2024092301101140000_2024.09.18.613405v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature11283"},{"key":"2024092301101140000_2024.09.18.613405v1.5","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/s41573-022-00391-w","article-title":"The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics","volume":"21","year":"2022","journal-title":"Nature reviews. 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