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We screened different essential and non\u2010essential amino acids for the ability to stimulate lysosomal biogenesis and, interestingly, found an essential amino acid L\u2010leucine as the most potent one in stimulating lysosomal biogenesis in astrocytes. However, D\u2010leucine remained weaker than L\u2010leucine in terms of stimulation of lysosomal biogenesis. Accordingly, L\u2010leucine increased autophagy in cultured brain cells and in\u00a0vivo in the brain of\n                    <jats:italic>5XFAD<\/jats:italic>\n                    mice, one of the animal models of Alzheimer's disease (AD). L\u2010Leucine also stimulated the uptake and degradation of amyloid\u2010\u03b2 in astrocytes and reduced the plaque load and improved cognitive functions in\n                    <jats:italic>5XFAD<\/jats:italic>\n                    mice. Although L\u2010leucine was discovered about 200\u2009years back, until now, no receptor has been identified for L\u2010leucine. Here, we noticed that L\u2010leucine binds to the ligand\u2010binding domain of peroxisome proliferator\u2010activated receptor \u03b1 (PPAR\u03b1) to activate this nuclear hormone receptor. Accordingly, L\u2010leucine remained ineffective in increasing lysosomal biogenesis and autophagy in\n                    <jats:italic>PPAR\u03b1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    brain cells. Lentiviral establishment of\n                    <jats:italic>full\u2010length PPAR\u03b1<\/jats:italic>\n                    , but not\n                    <jats:italic>Y314D\u2010PPAR\u03b1<\/jats:italic>\n                    , reinstated the autophagy\u2010stimulating effect of L\u2010leucine in\n                    <jats:italic>PPAR\u03b1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    astrocytes, emphasizing the importance of leucine's interaction with the Y314 residue. Moreover, oral L\u2010leucine decreased the plaque load and improved spatial learning and memory in\n                    <jats:italic>5XFAD<\/jats:italic>\n                    mice, but not in\n                    <jats:italic>5XFAD<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u0394PPAR\u03b1<\/jats:italic>\n                    <\/jats:sup>\n                    mice (\n                    <jats:italic>5XFAD<\/jats:italic>\n                    lacking\n                    <jats:italic>PPAR\u03b1<\/jats:italic>\n                    ), highlighting the involvement of PPAR\u03b1 in the neuroprotective effects of L\u2010leucine. These results may be beneficial for AD patients.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70432-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70432","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T13:45:44Z","timestamp":1775483144000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["L\u2010Leucine Upregulates Lysosomal Biogenesis and Autophagy to Lower Plaques in\n                    <scp>5XFAD<\/scp>\n                    Mouse Model of Alzheimer's Disease"],"prefix":"10.1111","volume":"170","author":[{"given":"Ramesh K.","family":"Paidi","sequence":"first","affiliation":[{"name":"Department of Neurological Sciences Rush University Medical Center  Chicago Illinois USA"},{"name":"Division of Research and Development Jesse Brown Veterans Affairs Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukhamoy","family":"Gorai","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences Rush University Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanta","family":"Mondal","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences Rush University Medical Center  Chicago Illinois USA"},{"name":"Division of Research and Development Jesse Brown Veterans Affairs Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6048-9598","authenticated-orcid":false,"given":"Kalipada","family":"Pahan","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences Rush University Medical Center  Chicago Illinois USA"},{"name":"Division of Research and Development Jesse Brown Veterans Affairs Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,6]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-018-0048-7"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5480-05.2006"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803336"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.1.275"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1515\/nipt-2023-0014"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3233\/ADR-210026"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14813"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-017-9771-4"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700149"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0054-18.2018"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-023-00883-2"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1504890112"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102624"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.426536"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.2.1344"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1305623110"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25767-1"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI161987"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105318"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111058"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.365767"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.365148"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.610659"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.346932"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2015.11.011"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-019-01649-y"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2021.11.021"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.05.013"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb9036"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-007-9340-y"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0138-8"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/35013000"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.338012"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-024-00940-4"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0342-4"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2019.1596488"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2025.150089"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2016.02.002"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3233\/ADR-230179"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0103606"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0130398"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.07.027"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM2003ra020003"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1202-06.2006"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100144"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-020-09979-8"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-021-10028-1"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200279"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112717"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113086"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1802021115"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.136654"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.14.5119-5128.2000"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201303671"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells122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