{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T17:05:41Z","timestamp":1777395941393,"version":"3.51.4"},"reference-count":55,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2018,5,26]],"date-time":"2018-05-26T00:00:00Z","timestamp":1527292800000},"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":[[2018,6,8]]},"abstract":"<jats:p>Deregulation of the amyloid-\u03b2 protein precursor (A\u03b2PP) plays a critical role in the neurodegenerative cascade of Alzheimer\u2019s disease (AD). Significantly, common functional polymorphisms in the 5,10-methylenetetrahydrofolate reductase ( MTHFR) gene are a risk factor for the development of late-onset AD. Reduced MTHFR activity is associated with alterations in folate and homocysteine metabolism. Here, we first show that in young MTHFR knockout mice, mild and severe MTHFR deficiency markedly increase cortical and hippocampal A\u03b2PP phosphorylation at the regulatory Thr668 site. However, the hippocampus is especially vulnerable to the effects of aging and mild MTHFR deficiency. Notably, the effects of severe MTHFR deficiency in young mice are recapitulated by prolonged dietary folate deficiency in old mice, which leads to regional brain accumulation of cystathionine due to impaired methylation of homocysteine. The incremental A\u03b2PP phosphorylation at Thr668 mediated by severe genetic-or diet-induced impairment of the folate cycle correlates with enhanced accumulation of demethylated protein phosphatase 2A (PP2A), and activation of glycogen synthase kinase-3\u03b2 (GSK-3\u03b2). Lastly, we show that severe disturbances in folate metabolism can also affect A\u03b2PP expression levels in a brain region specific manner. Together our findings identify a novel link between genetic MTHFR deficiency, activation of GSK-3\u03b2, demethylation of PP2A, and enhanced phosphorylation of A\u03b2PP at Thr668, which is known to critically influence neuronal A\u03b2PP function and pathological amyloidogenic processing. Deregulation of A\u03b2PP provides a novel mechanism by which common human MTHFR polymorphisms may interact with dietary folate deficiency to alter neuronal homeostasis and increase the risk for sporadic AD.<\/jats:p>","DOI":"10.3233\/jad-180032","type":"journal-article","created":{"date-parts":[[2018,5,29]],"date-time":"2018-05-29T11:21:34Z","timestamp":1527592894000},"page":"223-237","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":13,"title":["Methylenetetrahydrofolate Reductase Deficiency Deregulates Regional Brain Amyloid-\u03b2 Protein Precursor Expression and Phosphorylation Levels"],"prefix":"10.1177","volume":"64","author":[{"given":"Alexander","family":"Hoffman","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia"},{"name":"Hunter Medical Research Institute, New Lambton Heights, NSW, 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