{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T09:46:28Z","timestamp":1793699188834,"version":"4.5.1"},"reference-count":44,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T00:00:00Z","timestamp":1552953600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2019,4,23]]},"abstract":"<jats:p>Epidemiological studies suggest that individuals with diabetes mellitus are at greater risk of developing Alzheimer\u2019s disease. A well-known insulin-sensitizing drug and the most widely prescribed oral medication for diabetes is metformin. There is evidence that metformin acts in a neuroprotective manner via the AMPK\/mTOR pathway by inhibiting the tau phosphorylation. In addition, it is known that metformin upregulates Fgf21, which in turn activates the AMPK\/mTOR pathway and mediates neuroprotection. Thus, metformin-induced Fgf21 release may be involved in AMPK\/mTOR activation. However, some studies reported that metformin causes cognition impairment. Due to the controversial data on the neuroprotective properties of metformin, we treated Apolipoprotein E deficient ( ApoE\u2013 \/\u2013) mice, a mouse model of tauopathy, with metformin for 18 weeks. Metformin-treated mice revealed increased expression of lipogenic genes, i.e., lxr \u03b1 and srebp1c. In line with this, metformin caused an increase in plasma triglyceride leading to enhanced gliosis as indicated by an increase of GFAP-positive cells. Although the systemic Fgf21 concentration was increased, metformin did not activate the FgfR1c\/AMPK\/mTOR pathway suggesting a Fgf21-resistant state. Further, metformin-treated mice showed increased tau phosphorylation and reduced numbers of NeuN-and PSD95-positive cells. Thus, metformin-associated lipogenesis as well as inflammation aggravated neurodegenerative processes in ApoE\u2013 \/\u2013 mice. Consequently, this study supports previous observations showing that metformin causes impairment of cognition.<\/jats:p>","DOI":"10.3233\/jad-181017","type":"journal-article","created":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T17:22:35Z","timestamp":1553016155000},"page":"1415-1427","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":34,"title":["Metformin Therapy Aggravates Neurodegenerative Processes in\n                    <i>ApoE<\/i>\n                    \u2013\/\u2013 Mice"],"prefix":"10.1177","volume":"68","author":[{"given":"Angela","family":"Kuhla","sequence":"first","affiliation":[{"name":"Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Brichmann","sequence":"additional","affiliation":[{"name":"Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"R\u00fchlmann","sequence":"additional","affiliation":[{"name":"Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Thiele","sequence":"additional","affiliation":[{"name":"Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lou","family":"Meuth","sequence":"additional","affiliation":[{"name":"Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Vollmar","sequence":"additional","affiliation":[{"name":"Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,3,19]]},"reference":[{"key":"ref001","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2009.02.013"},{"key":"ref002","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2011.233"},{"key":"ref003","doi-asserted-by":"crossref","unstructured":"CorreiaSC, SantosRX, PerryG,             ZhuX, MoreiraPI, SmithMA             (2011) Insulin-resistant brain state: The culprit in             sporadic Alzheimer\u2019s disease? 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