{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T21:37:45Z","timestamp":1771537065570,"version":"3.50.1"},"reference-count":89,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["NIH AG044871-01 (HWQ)"],"award-info":[{"award-number":["NIH AG044871-01 (HWQ)"]}]},{"name":"Bennett Foundation (HWQ)","award":["NIH AG044871-01 (HWQ)"],"award-info":[{"award-number":["NIH AG044871-01 (HWQ)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Alzheimer\u2019s disease (AD)-affected brain is known to be deficient in the utilization of glucose, its main energy substrate, and systemic diabetes is a significant risk factor for AD. In the course of biochemical and molecular investigations into this puzzling relationship, it has been shown that resistance to insulin action is a prominent feature of early stages of AD in the brain, thereby contributing to an energy failure state and a decline in synaptic function. In one AD-like cellular model, we found that \u03b2-amyloid (A\u03b2) accumulation inhibited insulin signaling and cell viability through an alteration of the PI3K\/PDK-1\/Akt signal pathway, an effect overcome by mTORC2 stimulation. A PDK-1 allosteric agonist, PS48, as well as newly synthesized analogs, were also found to reverse the metabolic defects caused by intracellular A\u03b242 accumulation. In vivo, we previously showed that oral dosing of PS48 significantly improves learning and memory in APP\/PS1 transgenic mice. Herein, we present evidence using unbiased immunohistological quantification and Western blot analyses demonstrating that ingested PS48 crosses into brain tissue where it targeted Akt and GSK3-\u03b2 activities. Beneficial effects on neuronal number and Tau phosphorylation were found. Not unexpectedly, A\u03b2 levels remained unchanged. These results support a path toward a future therapeutic trial of this untested strategy and agent in humans.<\/jats:p>","DOI":"10.3390\/ijms26083473","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T03:32:53Z","timestamp":1744169573000},"page":"3473","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Target Validation Studies of PS48, a PDK-1 Allosteric Agonist, for the Treatment of Alzheimer\u2019s Disease Phenotype in APP\/PS1 Transgenic Mice"],"prefix":"10.3390","volume":"26","author":[{"given":"Henry W.","family":"Querfurth","sequence":"first","affiliation":[{"name":"Tufts Medical Center, Department of Neurology and Tufts University School of Medicine, Department of Neuroscience, 800 Washington St., and 136 Harrison Ave., Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2983-7870","authenticated-orcid":false,"given":"Cynthia","family":"Lemere","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, ARCND, 60 Fenwood Rd., Hale Bldg. for Transformative Medicine, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Ciola","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, ARCND, 60 Fenwood Rd., Hale Bldg. for Transformative Medicine, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5220-852X","authenticated-orcid":false,"given":"Daniel","family":"Havas","sequence":"additional","affiliation":[{"name":"Psychogenics Inc., 215 College Rd., Paramus, NJ 07652, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7463-3295","authenticated-orcid":false,"given":"Weiming","family":"Xia","sequence":"additional","affiliation":[{"name":"Chobanian and Avedisian School of Medicine, Department of Pharmacology, Physiology and Biophysics, Boston University, 72 E. Concord St., Boston, MA 02118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han Kyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Tufts Medical Center, Department of Neurology, 800 Washington St., Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1212\/01.WNL.0000140292.04932.87","article-title":"Hyperinsulinemia and risk of Alzheimer disease","volume":"63","author":"Luchsinger","year":"2004","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.jalz.2007.07.005","article-title":"Primary prevention of dementia","volume":"3","author":"Patterson","year":"2007","journal-title":"Alzheimers Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/j.1445-5994.2012.02758.x","article-title":"Diabetes as a risk factor for dementia and mild cognitive impairment: A meta-analysis of longitudinal studies","volume":"42","author":"Cheng","year":"2012","journal-title":"Intern. Med. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/S1474-4422(05)70284-2","article-title":"Risk of dementia in diabetes mellitus: A systematic review","volume":"5","author":"Biessels","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/S1474-4422(14)70136-X","article-title":"Potential for primary prevention of Alzheimer\u2019s disease: An analysis of population-based data","volume":"13","author":"Norton","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","article-title":"Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium","volume":"278","author":"Farrer","year":"1997","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1126\/science.8346443","article-title":"Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families","volume":"261","author":"Corder","year":"1993","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1385\/JMN:23:3:157","article-title":"APOE genotype effects on Alzheimer\u2019s disease onset and epidemiology","volume":"23","author":"Ashford","year":"2004","journal-title":"J. Mol. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.neurobiolaging.2009.04.021","article-title":"Apolipoprotein E: Implications for AD neurobiology, epidemiology and risk assessment","volume":"32","author":"Schipper","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.2337\/diabetes.51.4.1256","article-title":"Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study","volume":"51","author":"Peila","year":"2002","journal-title":"Diabetes"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1212\/01.wnl.0000310646.32212.3a","article-title":"Impaired insulin secretion increases the risk of Alzheimer disease","volume":"71","author":"Ronnemaa","year":"2008","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1001\/jamaneurol.2015.0613","article-title":"Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle-Aged Adults at Risk for Alzheimer Disease","volume":"72","author":"Willette","year":"2015","journal-title":"JAMA Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/ana.25826","article-title":"Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function","volume":"88","author":"Arvanitakis","year":"2020","journal-title":"Ann. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","article-title":"AKT\/PKB signaling: Navigating downstream","volume":"129","author":"Manning","year":"2007","journal-title":"Cell"},{"key":"ref_15","first-page":"19","article-title":"Physiological regulation of Akt activity and stability","volume":"2","author":"Liao","year":"2010","journal-title":"Am. J. Transl. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation and regulation of Akt\/PKB by the rictor-mTOR complex","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6473","DOI":"10.1038\/onc.2008.313","article-title":"PI3K\/Akt: Getting it right matters","volume":"27","author":"Franke","year":"2008","journal-title":"Oncogene"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1002\/med.21867","article-title":"Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases","volume":"42","author":"Wang","year":"2022","journal-title":"Med. Res. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"309","DOI":"10.3233\/JAD-2006-9S335","article-title":"GSK-3 is essential in the pathogenesis of Alzheimer\u2019s disease","volume":"9","author":"Takashima","year":"2006","journal-title":"J. Alzheimers Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0301-0082(01)00011-9","article-title":"The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling","volume":"65","author":"Grimes","year":"2001","journal-title":"Prog. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sayas, C.L., and Avila, J. (2021). GSK-3 and Tau: A Key Duet in Alzheimer\u2019s Disease. Cells, 10.","DOI":"10.3390\/cells10040721"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gejl, M., Gjedde, A., Egefjord, L., Moller, A., Hansen, S.B., Vang, K., Rodell, A., Braendgaard, H., Gottrup, H., and Schacht, A. (2016). In Alzheimer\u2019s Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front. Aging Neurosci., 8.","DOI":"10.3389\/fnagi.2016.00108"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/j.1463-1326.2012.01663.x","article-title":"GLP-1 receptor activated insulin secretion from pancreatic beta-cells: Mechanism and glucose dependence","volume":"15","author":"Meloni","year":"2013","journal-title":"Diabetes Obes. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"398","DOI":"10.2337\/dc21-1136","article-title":"Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial","volume":"45","author":"Kullmann","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/ana.24439","article-title":"Effect of pioglitazone medication on the incidence of dementia","volume":"78","author":"Heneka","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3233\/JAD-141959","article-title":"A phase II trial of tideglusib in Alzheimer\u2019s disease","volume":"45","author":"Lovestone","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1001\/jamaneurol.2020.1840","article-title":"Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial","volume":"77","author":"Craft","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/S1474-4422(20)30173-3","article-title":"Effect of dulaglutide on cognitive impairment in type 2 diabetes: An exploratory analysis of the REWIND trial","volume":"19","author":"Gerstein","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1471-4159.2004.02949.x","article-title":"Activation of Akt\/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer\u2019s disease pathology","volume":"93","author":"Griffin","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.exger.2013.02.025","article-title":"PI3-kinase\/Akt\/mTOR signaling: Impaired on\/off switches in aging, cognitive decline and Alzheimer\u2019s disease","volume":"48","year":"2013","journal-title":"Exp. Gerontol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1750-1326-4-14","article-title":"The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events","volume":"4","author":"Bhaskar","year":"2009","journal-title":"Mol. Neurodegener."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s00401-002-0657-y","article-title":"Role of protein kinase B in Alzheimer\u2019s neurofibrillary pathology","volume":"105","author":"Pei","year":"2003","journal-title":"Acta Neuropathol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ma, T., Hoeffer, C.A., Capetillo-Zarate, E., Yu, F., Wong, H., Lin, M.T., Tampellini, D., Klann, E., Blitzer, R.D., and Gouras, G.K. (2010). Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer\u2019s disease. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012845"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1089\/ars.2016.6860","article-title":"Reactive Oxygen Species-Mediated Loss of Synaptic Akt1 Signaling Leads to Deficient Activity-Dependent Protein Translation Early in Alzheimer\u2019s Disease","volume":"27","author":"Ahmad","year":"2017","journal-title":"Antioxid. Redox Signal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/path.2912","article-title":"Deficient brain insulin signalling pathway in Alzheimer\u2019s disease and diabetes","volume":"225","author":"Liu","year":"2011","journal-title":"J. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3233\/JAD-2005-7107","article-title":"Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer\u2019s disease\u2014Is this type 3 diabetes?","volume":"7","author":"Steen","year":"2005","journal-title":"J. Alzheimers Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1091\/mbc.e08-07-0777","article-title":"The insulin\/Akt signaling pathway is targeted by intracellular beta-amyloid","volume":"20","author":"Lee","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1172\/JCI59903","article-title":"Demonstrated brain insulin resistance in Alzheimer\u2019s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline","volume":"122","author":"Talbot","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1096\/fj.03-0978fje","article-title":"Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer\u2019s disease","volume":"18","author":"Ho","year":"2004","journal-title":"FASEB J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/nchembio.208","article-title":"Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1","volume":"5","author":"Hindie","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.semcancer.2017.05.011","article-title":"AGC kinases, mechanisms of regulation and innovative drug development","volume":"48","author":"Leroux","year":"2018","journal-title":"Semin. Cancer Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1038\/emboj.2008.120","article-title":"The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C","volume":"27","author":"Facchinetti","year":"2008","journal-title":"EMBO J."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Querfurth, H., Marshall, J., Parang, K., Rioult-Pedotti, M.S., Tiwari, R., Kwon, B., Reisinger, S., and Lee, H.K. (2022). A PDK-1 allosteric agonist neutralizes insulin signaling derangements and beta-amyloid toxicity in neuronal cells and in vitro. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0261696"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"114183","DOI":"10.1016\/j.bbr.2022.114183","article-title":"A PDK-1 allosteric agonist improves spatial learning and memory in a betaAPP\/PS-1 transgenic mouse-high fat diet intervention model of Alzheimer\u2019s disease","volume":"438","author":"Querfurth","year":"2023","journal-title":"Behav. Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kimura, T., Sharma, G., Ishiguro, K., and Hisanaga, S.I. (2018). Phospho-Tau Bar Code: Analysis of Phosphoisotypes of Tau and Its Application to Tauopathy. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00044"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4683","DOI":"10.1021\/jm9001499","article-title":"3,5-Diphenylpent-2-enoic acids as allosteric activators of the protein kinase PDK1: Structure-activity relationships and thermodynamic characterization of binding as paradigms for PIF-binding pocket-targeting compounds","volume":"52","author":"Stroba","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4380","DOI":"10.1093\/emboj\/20.16.4380","article-title":"The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB","volume":"20","author":"Biondi","year":"2001","journal-title":"EMBO J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1093\/emboj\/19.5.979","article-title":"Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA","volume":"19","author":"Biondi","year":"2000","journal-title":"EMBO J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bst0290001","article-title":"Discovery of PDK1, one of the missing links in insulin signal transduction. Colworth Medal Lecture","volume":"29","author":"Alessi","year":"2001","journal-title":"Biochem. Soc. Trans."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.stem.2010.11.015","article-title":"Reprogramming of human primary somatic cells by OCT4 and chemical compounds","volume":"7","author":"Zhu","year":"2010","journal-title":"Cell Stem Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1523\/JNEUROSCI.4477-10.2011","article-title":"Phosphoinositide-3-kinase activation controls synaptogenesis and spinogenesis in hippocampal neurons","volume":"31","author":"Cuesto","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1089\/brain.2019.0676","article-title":"Differentiation of Early Alzheimer\u2019s Disease, Mild Cognitive Impairment, and Cognitively Healthy Elderly Samples Using Multimodal Neuroimaging Indices","volume":"9","author":"Joshi","year":"2019","journal-title":"Brain Connect."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.brainres.2017.10.025","article-title":"Evaluating functional connectivity of executive control network and frontoparietal network in Alzheimer\u2019s disease","volume":"1678","author":"Zhao","year":"2018","journal-title":"Brain Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1007\/s11064-008-9714-9","article-title":"Inhibition of Wnt and PI3K signaling modulates GSK-3beta activity and induces morphological changes in cortical neurons: Role of tau phosphorylation","volume":"33","author":"Massieu","year":"2008","journal-title":"Neurochem. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1097\/00001756-200302100-00020","article-title":"Glycogen synthase kinase-3 beta-mediated tau phosphorylation in cultured cell lines","volume":"14","author":"Lee","year":"2003","journal-title":"Neuroreport"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.bbadis.2003.09.001","article-title":"Akt\/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro","volume":"1639","author":"Pyo","year":"2003","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.psyneuen.2014.06.005","article-title":"Prediabetes-induced vascular alterations exacerbate central pathology in APPswe\/PS1dE9 mice","volume":"48","year":"2014","journal-title":"Psychoneuroendocrinology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.nbd.2017.01.004","article-title":"Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, beta-amyloid accumulation and cognitive decline in the APP\/PSEN1 mouse model of Alzheimer\u2019s disease","volume":"100","author":"Walker","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6269","DOI":"10.1016\/j.febslet.2006.10.033","article-title":"PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners","volume":"580","author":"Liu","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1006\/abbi.1998.0813","article-title":"Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules","volume":"357","author":"Sengupta","year":"1998","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1074\/jbc.M206236200","article-title":"Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed sites. Differential impact on microtubule binding","volume":"278","author":"Cho","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3429","DOI":"10.1111\/j.1460-9568.2007.05955.x","article-title":"Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregation","volume":"26","author":"Liu","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/j.1471-4159.2004.02155.x","article-title":"Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau\u2019s ability to bind and stabilize microtubules","volume":"88","author":"Cho","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1016\/j.str.2015.06.002","article-title":"Structural Impact of Tau Phosphorylation at Threonine 231","volume":"23","author":"Schwalbe","year":"2015","journal-title":"Structure"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s40478-018-0557-6","article-title":"Phosphorylation of different tau sites during progression of Alzheimer\u2019s disease","volume":"6","author":"Neddens","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Quartey, M.O., Nyarko, J.N.K., Maley, J.M., Barnes, J.R., Bolanos, M.A.C., Heistad, R.M., Knudsen, K.J., Pennington, P.R., Buttigieg, J., and De Carvalho, C.E. (2021). The Abeta(1-38) peptide is a negative regulator of the Abeta(1-42) peptide implicated in Alzheimer disease progression. Sci. Rep., 11.","DOI":"10.1038\/s41598-020-80164-w"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e958","DOI":"10.1212\/WNL.0000000000013228","article-title":"Association of CSF Abeta(38) Levels With Risk of Alzheimer Disease-Related Decline","volume":"98","author":"Cullen","year":"2022","journal-title":"Neurology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"67808","DOI":"10.18632\/oncotarget.12179","article-title":"High fat diet exacerbates Alzheimer\u2019s disease-related pathology in APPswe\/PS1 mice","volume":"7","author":"Theriault","year":"2016","journal-title":"Oncotarget"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e12818","DOI":"10.1111\/acel.12818","article-title":"High-fat diet protects the blood-brain barrier in an Alzheimer\u2019s disease mouse model","volume":"17","author":"Goez","year":"2018","journal-title":"Aging Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3712","DOI":"10.1523\/JNEUROSCI.0059-07.2007","article-title":"Pyrrolidine dithiocarbamate activates Akt and improves spatial learning in APP\/PS1 mice without affecting beta-amyloid burden","volume":"27","author":"Malm","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.neuropharm.2017.10.028","article-title":"Direct pharmacological Akt activation rescues Alzheimer\u2019s disease like memory impairments and aberrant synaptic plasticity","volume":"128","author":"Yi","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"10581","DOI":"10.1073\/pnas.1202810109","article-title":"Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death","volume":"109","author":"Jo","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","first-page":"1335","article-title":"Neuroprotective effects of salidroside through PI3K\/Akt pathway activation in Alzheimer\u2019s disease models","volume":"10","author":"Zhang","year":"2016","journal-title":"Drug Des. Devel Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"174772","DOI":"10.1016\/j.ejphar.2022.174772","article-title":"Tanshinone IIA regulates glycogen synthase kinase-3beta-related signaling pathway and ameliorates memory impairment in APP\/PS1 transgenic mice","volume":"918","author":"Peng","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.3233\/JAD-230551","article-title":"Reduction of Phosphorylated Tau in Alzheimer\u2019s Disease Induced Pluripotent Stem Cell-Derived Neuro-Spheroids by Rho-Associated Coiled-Coil Kinase Inhibitor Fasudil","volume":"96","author":"Giunti","year":"2023","journal-title":"J. Alzheimers Dis."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Long, H.Z., Cheng, Y., Zhou, Z.W., Luo, H.Y., Wen, D.D., and Gao, L.C. (2021). PI3K\/AKT Signal Pathway: A Target of Natural Products in the Prevention and Treatment of Alzheimer\u2019s Disease and Parkinson\u2019s Disease. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.648636"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1016\/j.peptides.2006.07.001","article-title":"Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats","volume":"27","author":"Oomura","year":"2006","journal-title":"Peptides"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1358\/dnp.2004.17.10.873917","article-title":"Inhibitors beta-amyloid-induced toxicity by modulating the Akt signaling pathway","volume":"17","author":"Nakagami","year":"2004","journal-title":"Drug News Perspect."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1007\/s11030-023-10671-1","article-title":"Identification of potential Akt activators: A ligand and structure-based computational approach","volume":"28","author":"Kumar","year":"2024","journal-title":"Mol. Divers."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/alzrt265","article-title":"Dietary regulation of PI3K\/AKT\/GSK-3beta pathway in Alzheimer\u2019s disease","volume":"6","author":"Kitagishi","year":"2014","journal-title":"Alzheimers Res. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Mordhorst, B.R., Kerns, K.C., Schauflinger, M., Zigo, M., Murphy, S.L., Ross, R.M., Wells, K.D., Green, J.A., Sutovsky, P., and Prather, R.S. (2019). Pharmacologic treatment with CPI-613 and PS48 decreases mitochondrial membrane potential and increases quantity of autolysosomes in porcine fibroblasts. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-45850-4"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/mrd.22474","article-title":"PS48 can replace bovine serum albumin in pig embryo culture medium, and improve in vitro embryo development by phosphorylating AKT","volume":"82","author":"Spate","year":"2015","journal-title":"Mol. Reprod. Dev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1001\/jama.2023.13239","article-title":"Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial","volume":"330","author":"Sims","year":"2023","journal-title":"JAMA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"362","DOI":"10.14283\/jpad.2023.30","article-title":"Lecanemab: Appropriate Use Recommendations","volume":"10","author":"Cummings","year":"2023","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1370\/afm.3050","article-title":"Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis","volume":"22","author":"Ebell","year":"2024","journal-title":"Ann. Fam. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.3233\/JAD-161256","article-title":"Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer\u2019s Disease Biomarkers: A Pilot Clinical Trial","volume":"57","author":"Craft","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1080\/14756366.2018.1553167","article-title":"The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1","volume":"34","author":"Xu","year":"2019","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/hmg\/ddh019","article-title":"Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: Evidence for augmentation of a 42-specific gamma secretase","volume":"13","author":"Jankowsky","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainresbull.2015.12.003","article-title":"Toward more predictive genetic mouse models of Alzheimer\u2019s disease","volume":"122","author":"Onos","year":"2016","journal-title":"Brain Res. Bull."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3473\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:12:18Z","timestamp":1760029938000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3473"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,8]]},"references-count":89,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26083473"],"URL":"https:\/\/doi.org\/10.3390\/ijms26083473","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,8]]}}}