{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T11:17:49Z","timestamp":1781349469123,"version":"3.54.1"},"reference-count":109,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 113-2112-M-002-024"],"award-info":[{"award-number":["NSTC 113-2112-M-002-024"]}]},{"name":"National Science and Technology Council","award":["NSTC 112-2112-M-002-033"],"award-info":[{"award-number":["NSTC 112-2112-M-002-033"]}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST 110-2112-M-002-004"],"award-info":[{"award-number":["MOST 110-2112-M-002-004"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) remains a significant public health challenge, with current treatments limited partly due to the difficulty of delivering therapeutics across the blood\u2013brain barrier (BBB). The nose-to-brain (N-2-B) pathway offers a promising alternative to circumvent the BBB, but no drugs have yet been clinically applied via this route for AD. Mild stress is thought to activate intrinsic protective mechanisms against neurodegeneration, but traditional methods lack specificity and practicality. To address this, we propose the inhalation of mildly heated air as thermal stimulation, which utilizes the N-2-B pathway to induce mild stress and stimulate cerebral activity. This study employs thermal cycling-hyperthermia (TC-HT) in developing thermal cycling-stimulation via nasal inhalation (TCSNI), providing cyclic stimulation to maintain pathway activity while minimizing thermal injury. In C57BL\/6 mice, TCSNI showed no adverse olfactory effects. In \u03b2-amyloid (A\u03b2)-treated mice, TCSNI significantly enhanced cognitive performance in Y-maze and novel object recognition (NOR) assessments, suggesting cognitive improvement. Mice hippocampal protein analyses indicated a reduction in A\u03b2 accumulation, alongside increased expression of heat shock protein 70 (HSP70), insulin-degrading enzyme (IDE), and phosphorylated Akt (p-Akt). These results suggest that N-2-B-delivered TCSNI effectively modulates protein expression and enhances cognitive function, highlighting its potential for further exploration in AD treatment.<\/jats:p>","DOI":"10.3390\/ijms262010236","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T14:24:02Z","timestamp":1761056642000},"page":"10236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Thermal Cycling Stimulation via Nasal Inhalation Attenuates A\u03b225\u201335-Induced Cognitive Deficits in C57BL\/6 Mice"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9828-9700","authenticated-orcid":false,"given":"Guan-Bo","family":"Lin","sequence":"first","affiliation":[{"name":"Laboratory for Medical Physics & Biomedical Engineering, Department of Physics, National Taiwan University, Taipei 106319, Taiwan"},{"name":"Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6023-8235","authenticated-orcid":false,"given":"Hsu-Hsiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan"},{"name":"Biophysics Division, Graduate Institute of Applied Physics, National Taiwan University, Taipei 106319, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6659-6236","authenticated-orcid":false,"given":"Yu-Yi","family":"Kuo","sequence":"additional","affiliation":[{"name":"Laboratory for Medical Physics & Biomedical Engineering, Department of Physics, National Taiwan University, Taipei 106319, Taiwan"},{"name":"Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4715-6403","authenticated-orcid":false,"given":"You-Ming","family":"Chen","sequence":"additional","affiliation":[{"name":"Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan"},{"name":"Biophysics Division, Graduate Institute of Applied Physics, National Taiwan University, Taipei 106319, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1150-5006","authenticated-orcid":false,"given":"Fang-Tzu","family":"Hsu","sequence":"additional","affiliation":[{"name":"Laboratory for Medical Physics & Biomedical Engineering, Department of Physics, National Taiwan University, Taipei 106319, Taiwan"},{"name":"Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan"},{"name":"Biophysics Division, Graduate Institute of Applied Physics, National Taiwan University, Taipei 106319, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Kung","sequence":"additional","affiliation":[{"name":"Laboratory for Medical Physics & Biomedical Engineering, Department of Physics, National Taiwan University, Taipei 106319, Taiwan"},{"name":"Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien","family":"Ching","sequence":"additional","affiliation":[{"name":"Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan"},{"name":"Biophysics Division, Graduate Institute of Applied Physics, National Taiwan University, Taipei 106319, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9792-7034","authenticated-orcid":false,"given":"Chih-Yu","family":"Chao","sequence":"additional","affiliation":[{"name":"Laboratory for Medical Physics & Biomedical Engineering, Department of Physics, National Taiwan University, Taipei 106319, Taiwan"},{"name":"Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan"},{"name":"Biophysics Division, Graduate Institute of Applied Physics, National Taiwan University, Taipei 106319, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sun, X., Chen, W.D., and Wang, Y.D. (2015). \u03b2-Amyloid: The key peptide in the pathogenesis of Alzheimer\u2019s disease. Front. Pharmacol., 6.","DOI":"10.3389\/fphar.2015.00221"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1089\/ars.2011.4173","article-title":"Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation","volume":"16","author":"Leuner","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S0301-0082(00)00015-0","article-title":"The role of oxidative stress in the toxicity induced by amyloid beta-peptide in Alzheimer\u2019s disease","volume":"62","author":"Miranda","year":"2000","journal-title":"Prog. Neurobiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/nn.2583","article-title":"Amyloid-beta-induced neuronal dysfunction in Alzheimer\u2019s disease: From synapses toward neural networks","volume":"13","author":"Palop","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.molmed.2007.12.002","article-title":"Amyloid beta, mitochondrial dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer\u2019s disease","volume":"14","author":"Reddy","year":"2008","journal-title":"Trends Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/aps.2017.28","article-title":"Amyloid beta: Structure, biology and structure-based therapeutic development","volume":"38","author":"Chen","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1111\/psyg.12944","article-title":"Aducanumab for the treatment of Alzheimer\u2019s disease: A systematic review","volume":"23","author":"Rahman","year":"2023","journal-title":"Psychogeriatrics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e3592","DOI":"10.1002\/brb3.3592","article-title":"Use of lecanemab for the treatment of Alzheimer\u2019s disease: A systematic review","volume":"14","author":"Hossain","year":"2024","journal-title":"Brain Behav."},{"key":"ref_10","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. Alzheimer\u2019s Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/hast.1264","article-title":"Alzheimer\u2019s and Aducanumab: Unjust Profits and False Hopes","volume":"51","author":"Fleck","year":"2021","journal-title":"Hastings Cent. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.jalz.2009.06.003","article-title":"Alzheimer\u2019s disease drug development and the problem of the blood-brain barrier","volume":"5","author":"Pardridge","year":"2009","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41392-023-01481-w","article-title":"The blood-brain barrier: Structure, regulation, and drug delivery","volume":"8","author":"Wu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_14","first-page":"533","article-title":"Hormetic modulation of aging and longevity by mild heat stress","volume":"3","author":"Rattan","year":"2006","journal-title":"Dose Response"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Schirrmacher, V. (2021). Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications. Biomedicines, 9.","DOI":"10.3390\/biomedicines9030293"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"127","DOI":"10.2114\/jpa2.29.127","article-title":"Beneficial effects of mild stress (hormetic effects): Dietary restriction and health","volume":"29","author":"Kouda","year":"2010","journal-title":"J. Physiol. Anthropol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1002\/jnr.23925","article-title":"Major pathogenic mechanisms in vascular dementia: Roles of cellular stress response and hormesis in neuroprotection","volume":"94","author":"Calabrese","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_18","first-page":"58","article-title":"Hormesis can and does work in humans","volume":"8","author":"Rattan","year":"2009","journal-title":"Dose Response"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.exger.2010.10.001","article-title":"Mild stress facilitates learning and exercise improves retention in aged mice","volume":"46","author":"Adlard","year":"2011","journal-title":"Exp. Gerontol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1023\/A:1010085823990","article-title":"Longevity and aging: Beneficial effects of exposure to mild stress","volume":"1","author":"Minois","year":"2000","journal-title":"Biogerontology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/mp.2009.130","article-title":"Predictable chronic mild stress improves mood, hippocampal neurogenesis and memory","volume":"16","author":"Parihar","year":"2011","journal-title":"Mol. Psychiatry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.arr.2007.08.007","article-title":"Hormesis defined","volume":"7","author":"Mattson","year":"2008","journal-title":"Ageing Res. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13109","DOI":"10.3390\/ijms140713109","article-title":"Hormesis in aging and neurodegeneration-a prodigy awaiting dissection","volume":"14","author":"Mao","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_24","first-page":"238","article-title":"Hormesis, cell death, and regenerative medicine for neurode-generative diseases","volume":"11","author":"Wang","year":"2012","journal-title":"Dose Response"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.cmet.2023.12.022","article-title":"The hormesis principle of neuroplasticity and neuroprotection","volume":"36","author":"Mattson","year":"2024","journal-title":"Cell Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ibror.2018.11.002","article-title":"Mild heat stress induces hormetic effects in protecting the primary culture of mouse prefrontal cerebrocortical neurons from neuropathological alterations","volume":"5","author":"Mane","year":"2018","journal-title":"IBRO Rep."},{"key":"ref_27","first-page":"684283","article-title":"Alternative strategy for Alzheimer\u2019s disease: Stress response triggers","volume":"2012","year":"2012","journal-title":"Int. J. Alzheimer\u2019s Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"111509","DOI":"10.1016\/j.exger.2021.111509","article-title":"Sauna use as a lifestyle practice to extend healthspan","volume":"154","author":"Patrick","year":"2021","journal-title":"Exp. Gerontol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/j.1749-6632.2002.tb02085.x","article-title":"Exercise-induced modulation of antioxidant defense","volume":"959","author":"Ji","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"101221","DOI":"10.1016\/j.pmedr.2020.101221","article-title":"Does sauna bathing protect against dementia?","volume":"20","author":"Knekt","year":"2020","journal-title":"Prev. Med. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1093\/ageing\/afw212","article-title":"Sauna bathing is inversely associated with dementia and Alzheimer\u2019s disease in middle-aged Finnish men","volume":"46","author":"Laukkanen","year":"2017","journal-title":"Age Ageing"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1111\/jgs.14059","article-title":"Effects of Exercise on Cognition: The Finnish Alzheimer Disease Exercise Trial: A Randomized, Controlled Trial","volume":"64","author":"Savikko","year":"2016","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101108","DOI":"10.1016\/j.arr.2020.101108","article-title":"Exercise benefits on Alzheimer\u2019s disease: State-of-the-science","volume":"62","author":"Valenzuela","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1517\/17425247.2013.790887","article-title":"Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: An excellent platform for brain targeting","volume":"10","author":"Pardeshi","year":"2013","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Patharapankal, E.J., Ajiboye, A.L., Mattern, C., and Trivedi, V. (2023). Nose-to-Brain (N2B) Delivery: An Alternative Route for the Delivery of Biologics in the Management and Treatment of Central Nervous System Disorders. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16010066"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jconrel.2018.05.011","article-title":"Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs","volume":"281","author":"Agrawal","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.4103\/1673-5374.241458","article-title":"Nose-to-brain drug delivery approach: A key to easily accessing the brain for the treatment of Alzheimer\u2019s disease","volume":"13","author":"Alexander","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1007\/s13346-024-01558-1","article-title":"Insulin Delivery to the Brain via the Nasal Route: Unraveling the Potential for Alzheimer\u2019s Disease Therapy","volume":"14","author":"Wong","year":"2024","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1159\/000519915","article-title":"Effectiveness and Safety of Aromatherapy in Managing Behavioral and Psychological Symptoms of Dementia: A Mixed-Methods Systematic Review","volume":"11","author":"Li","year":"2021","journal-title":"Dement. Geriatr. Cogn. Dis. Extra"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1016\/j.gerinurse.2021.07.003","article-title":"Effects of olfactory stimulation on cognitive function and behavior problems in older adults with dementia: A systematic literature review","volume":"42","author":"Cha","year":"2021","journal-title":"Geriatr. Nurs."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"118180","DOI":"10.1016\/j.jep.2024.118180","article-title":"Essential oils for clinical aromatherapy: A comprehensive review","volume":"330","author":"Vora","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.physbeh.2013.08.006","article-title":"Cognitive-enhancing and antioxidant activities of inhaled coriander volatile oil in amyloid \u03b2(1-42) rat model of Alzheimer\u2019s disease","volume":"120","author":"Cioanca","year":"2013","journal-title":"Physiol. Behav."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/ffj.3435","article-title":"The effect of inhalation of essential oil from Rosmarinus officinalis on scopolamine--induced Alzheimer\u2019s type dementia model mice","volume":"33","author":"Satou","year":"2018","journal-title":"Flavour. Fragr. J."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Okuda, M., Fujita, Y., Takada-Takatori, Y., Sugimoto, H., and Urakami, K. (2020). Aromatherapy improves cognitive dysfunction in senescence-accelerated mouse prone 8 by reducing the level of amyloid beta and tau phosphorylation. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0240378"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1615\/CritRevBiomedEng.v34.i6.20","article-title":"Thermal therapy, part 1: An introduction to thermal therapy","volume":"34","author":"Habash","year":"2006","journal-title":"Crit. Rev. Biomed. Eng."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2107705","DOI":"10.1002\/smll.202107705","article-title":"Non-Invasive Thermal Therapy for Tissue Engineering and Regenerative Medicine","volume":"18","author":"Li","year":"2022","journal-title":"Small"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1177\/153537020322801023","article-title":"Clinical implications of thermal therapy in lifestyle-related diseases","volume":"228","author":"Biro","year":"2003","journal-title":"Exp. Biol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Hunt, A.P., Minett, G.M., Gibson, O.R., Kerr, G.K., and Stewart, I.B. (2020). Could Heat Therapy Be an Effective Treatment for Alzheimer\u2019s and Parkinson\u2019s Diseases? A Narrative Review. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01556"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1152\/japplphysiol.00168.2020","article-title":"Heat therapy: Possible benefits for cognitive function and the aging brain","volume":"129","author":"Deng","year":"2020","journal-title":"J. Appl. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Smadja, D.M., and Abreu, M.M. (2025). Hyperthermia and targeting heat shock proteins: Innovative approaches for neurodegenerative disorders and Long COVID. Front. Neurosci., 19.","DOI":"10.3389\/fnins.2025.1475376"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1080\/10409238.2017.1337707","article-title":"Multiple functions of insulin-degrading enzyme: A metabolic crosslight?","volume":"52","author":"Tundo","year":"2017","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"137337","DOI":"10.1016\/j.neulet.2023.137337","article-title":"Thermal cycling-hyperthermia ameliorates A\u03b225\u201335-induced cognitive impairment in C57BL\/6 mice","volume":"810","author":"Kuo","year":"2023","journal-title":"Neurosci. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1046\/j.1471-4159.2002.01151.x","article-title":"Stress-mediated signaling in PC12 cells\u2014The role of the small heat shock protein, Hsp27, and Akt in protecting cells from heat stress and nerve growth factor withdrawal","volume":"83","author":"Mearow","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Chen, W.T., Kuo, Y.Y., Lin, G.B., Lu, C.H., Hsu, H.P., Sun, Y.K., and Chao, C.Y. (2020). Thermal cycling protects SH-SY5Y cells against hydrogen peroxide and \u03b2-amyloid-induced cell injury through stress response mechanisms involving Akt pathway. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0240022"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3233\/JAD-2011-110104","article-title":"Upregulation of AKT attenuates amyloid-\u03b2-induced cell apoptosis","volume":"25","author":"Yin","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s12031-015-0622-6","article-title":"The Interplay of Akt and ERK in A\u03b2 Toxicity and Insulin-Mediated Protection in Primary Hippocampal Cell Culture","volume":"57","author":"Ghasemi","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Kommaddi, R.P., Gowaikar, R., Haseena, P.A., Diwakar, L., Singh, K., and Mondal, A. (2024). Akt activation ameliorates deficits in hippocampal-dependent memory and activity-dependent synaptic protein synthesis in an Alzheimer\u2019s disease mouse model. J. Biol. Chem., 300.","DOI":"10.1016\/j.jbc.2023.105619"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/S0002-9343(00)00671-9","article-title":"Benefits and risks of sauna bathing","volume":"110","author":"Hannuksela","year":"2001","journal-title":"Am. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1002\/j.2040-4603.2015.tb00645.x","article-title":"Cerebral Vascular Control and Metabolism in Heat Stress","volume":"5","author":"Bain","year":"2015","journal-title":"Compr. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Prieur, E.A.K., and Jadavji, N.M. (2019). Assessing Spatial Working Memory Using the Spontaneous Alternation Y-maze Test in Aged Male Mice. Bio Protoc., 9.","DOI":"10.21769\/BioProtoc.3162"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/978-1-4939-8994-2_10","article-title":"The Y-Maze for Assessment of Spatial Working and Reference Memory in Mice","volume":"1916","author":"Kraeuter","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_62","first-page":"55718","article-title":"Novel Object Recognition Test for the Investigation of Learning and Memory in Mice","volume":"126","author":"Lueptow","year":"2017","journal-title":"J. Vis. Exp."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Navarro, D., Gasparyan, A., Mart\u00ed Mart\u00ednez, S., D\u00edaz Mar\u00edn, C., Navarrete, F., Garc\u00eda Guti\u00e9rrez, M.S., and Manzanares, J. (2023). Methods to Identify Cognitive Alterations from Animals to Humans: A Translational Approach. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087653"},{"key":"ref_64","first-page":"53308","article-title":"Intracerebroventricular Injection of Amyloid-\u03b2 Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits","volume":"109","author":"Kim","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/0471142301.ns0824s48","article-title":"Simple behavioral assessment of mouse olfaction","volume":"48","author":"Yang","year":"2009","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Zhang, J., Zhao, Z., Sun, S., Li, J., Wang, Y., Dong, J., Yang, S., Lou, Y., Yang, J., and Li, W. (2022). Olfactory Evaluation in Alzheimer\u2019s Disease Model Mice. Brain Sci., 12.","DOI":"10.3390\/brainsci12050607"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"445","DOI":"10.31887\/DCNS.2013.15.4\/hjahn","article-title":"Memory loss in Alzheimer\u2019s disease","volume":"15","author":"Jahn","year":"2013","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Lu, R.C., Tan, M.S., Wang, H., Xie, A.M., Yu, J.T., and Tan, L. (2014). Heat shock protein 70 in Alzheimer\u2019s disease. BioMed Res. Int., 2014.","DOI":"10.1155\/2014\/435203"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s12192-017-0839-0","article-title":"Modulation of Alzheimer\u2019s amyloid \u03b2 peptide oligomerization and toxicity by extracellular Hsp70","volume":"23","author":"Rivera","year":"2018","journal-title":"Cell Stress Chaperones"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"25424823241307021","DOI":"10.1177\/25424823241307021","article-title":"Heat shock protein 70 in Alzheimer\u2019s disease and other dementias: A possible alternative therapeutic","volume":"9","year":"2025","journal-title":"J. Alzheimer\u2019s Dis. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s11064-010-0259-3","article-title":"Apoptosis inhibition can be threatening in A\u03b2-induced neuroinflammation, through promoting cell proliferation","volume":"36","author":"Abdi","year":"2011","journal-title":"Neurochem. Res."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Hoshino, T., Suzuki, K., Matsushima, T., Yamakawa, N., Suzuki, T., and Mizushima, T. (2013). Suppression of Alzheimer\u2019s disease-related phenotypes by geranylgeranylacetone in mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076306"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0002-9440(10)63822-9","article-title":"Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer\u2019s disease is associated with the apolipoprotein E-epsilon4 allele","volume":"162","author":"Cook","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"11120","DOI":"10.1523\/JNEUROSCI.2860-04.2004","article-title":"Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: Implications for Alzheimer\u2019s disease intervention","volume":"24","author":"Zhao","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"200","DOI":"10.5607\/en.2014.23.3.200","article-title":"Neuroprotection signaling of nuclear akt in neuronal cells","volume":"23","author":"Ahn","year":"2014","journal-title":"Exp. Neurobiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cell.2017.04.001","article-title":"AKT\/PKB Signaling: Navigating the Network","volume":"169","author":"Manning","year":"2017","journal-title":"Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1007\/s11064-013-1131-z","article-title":"Neuregulin1beta1 antagonizes apoptosis via ErbB4-dependent activation of PI3-kinase\/Akt in APP\/PS1 transgenic mice","volume":"38","author":"Cui","year":"2013","journal-title":"Neurochem. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"10960","DOI":"10.1523\/JNEUROSCI.1723-05.2005","article-title":"Intraneuronal beta-amyloid expression downregulates the Akt survival pathway and blunts the stress response","volume":"25","author":"Rosen","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.molbrainres.2003.08.018","article-title":"In vivo heat-shock response in the brain: Signalling pathway and transcription factor activation","volume":"119","author":"Maroni","year":"2003","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Jensen, C.S., Hasselbalch, S.G., Waldemar, G., and Simonsen, A.H. (2015). Biochemical Markers of Physical Exercise on Mild Cognitive Impairment and Dementia: Systematic Review and Perspectives. Front. Neurol., 6.","DOI":"10.3389\/fneur.2015.00187"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1186\/s40001-023-01512-w","article-title":"The FDA-approved anti-amyloid-\u03b2 monoclonal antibodies for the treatment of Alzheimer\u2019s disease: A systematic review and meta-analysis of randomized controlled trials","volume":"28","author":"Wu","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13195-024-01482-z","article-title":"Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer\u2019s disease: A randomized, controlled clinical trial","volume":"16","author":"Ornish","year":"2024","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1097\/00007890-200104150-00007","article-title":"Protective effect of heat preconditioning of rat liver graft resulting in improved transplant survival","volume":"71","author":"Matsumoto","year":"2001","journal-title":"Transplantation"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1016\/j.bbagen.2009.01.004","article-title":"Hormesis, aging and longevity","volume":"1790","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s10522-020-09870-2","article-title":"Characterisation of the positive effects of mild stress on ageing and resistance to stress","volume":"21","year":"2020","journal-title":"Biogerontology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.neurobiolaging.2022.02.011","article-title":"Sauna-like conditions or menthol treatment reduce tau phosphorylation through mild hyperthermia","volume":"113","author":"Guisle","year":"2022","journal-title":"Neurobiol. Aging"},{"key":"ref_87","unstructured":"Crane, C.R., and Sanders, D.C. (1986). Inhalation Toxicology: VIII. Establishing Heat Tolerance Limits for Rats and Mice Subjected to Acute Exposures at Elevated Air Temperatures, Civil Aerospace Medical Institute. DOT\/FAA\/AM-86\/8."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Kassis, S., Grondin, M., and Averill-Bates, D.A. (2021). Heat shock increases levels of reactive oxygen species, autophagy and apoptosis. Biochim. Biophys. Acta Mol. Cell Res., 1868.","DOI":"10.1016\/j.bbamcr.2020.118924"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"513","DOI":"10.3109\/02656736.2014.971446","article-title":"Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review","volume":"30","author":"Slimen","year":"2014","journal-title":"Int. J. Hyperthermia"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"12902","DOI":"10.18632\/oncotarget.14186","article-title":"Reactive oxygen species mediate heat stress-induced apoptosis via ERK dephosphorylation and Bcl-2 ubiquitination in human umbilical vein endothelial cells","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"781","DOI":"10.3758\/BF03213109","article-title":"The nature and duration of adaptation following long-term odor exposure","volume":"58","author":"Dalton","year":"1996","journal-title":"Percept. Psychophys."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3743","DOI":"10.1007\/s00018-009-0111-6","article-title":"Mammalian olfactory receptors: Pharmacology, G protein coupling and desensitization","volume":"66","author":"Kato","year":"2009","journal-title":"Cell Mol. Life Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.physbeh.2017.04.006","article-title":"Habituation and adaptation to odors in humans","volume":"177","author":"Pellegrino","year":"2017","journal-title":"Physiol. Behav."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Kim, K., Bae, J., Jin, Y., and Moon, C. (2020). Odor habituation can modulate very early olfactory event-related potential. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-75263-7"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"fcae390","DOI":"10.1093\/braincomms\/fcae390","article-title":"Olfactory stimulation with multiple odorants prevents stress-induced cognitive and psychological alterations","volume":"6","author":"Bandiera","year":"2024","journal-title":"Brain Commun."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Okada, K., and Shimatani, K. (2024). Effect of olfactory stimulation from aromatherapy on the autonomic nervous activity during aerobic exercises. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-61732-w"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Scutigliani, E.M., Liang, Y., Crezee, H., Kanaar, R., and Krawczyk, P.M. (2021). Modulating the Heat Stress Response to Improve Hyperthermia-Based Anticancer Treatments. Cancers, 13.","DOI":"10.3390\/cancers13061243"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Ahmed, K., Zaidi, S.F., Rehman, M.U., Rehman, R., and Kondo, T. (2020). Hyperthermia and protein homeostasis: Cytoprotection and cell death. J. Therm. Biol., 91.","DOI":"10.1016\/j.jtherbio.2020.102615"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_100","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","author":"Karran","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1074\/jbc.M112.393108","article-title":"Insulin-degrading enzyme (IDE): A novel heat shock-like protein","volume":"288","author":"Tundo","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1523\/JNEUROSCI.20-05-01657.2000","article-title":"Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme","volume":"20","author":"Vekrellis","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"4162","DOI":"10.1073\/pnas.0230450100","article-title":"Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo","volume":"100","author":"Farris","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"101999","DOI":"10.1016\/j.arr.2023.101999","article-title":"Insulin-degrading enzyme: Roles and pathways in ameliorating cognitive impairment associated with Alzheimer\u2019s disease and diabetes","volume":"90","author":"Tian","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.molcel.2014.03.030","article-title":"Stress, inflammation, and defense of homeostasis","volume":"54","author":"Chovatiya","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/imr.12052","article-title":"Live or let die: Posttranscriptional gene regulation in cell stress and cell death","volume":"253","author":"Thomas","year":"2013","journal-title":"Immunol. Rev."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00497-016-0281-y","article-title":"Heat stress regimes for the investigation of pollen thermotolerance in crop plants","volume":"29","author":"Mesihovic","year":"2016","journal-title":"Plant Reprod."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Borgstedt, L., Bratke, S., Blobner, M., P\u00f6tzl, C., Ulm, B., Jungwirth, B., and Schmid, S. (2022). Isoflurane has no effect on cognitive or behavioral performance in a mouse model of early-stage Alzheimer\u2019s disease. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.1033729"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.3233\/JAD-201185","article-title":"Inhalational anesthetics do not deteriorate amyloid-\u03b2-derived pathophysiology in Alzheimer\u2019s disease: Investigations on the molecular, neuronal, and behavioral level","volume":"84","author":"Hofmann","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/10236\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T04:29:50Z","timestamp":1761193790000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/10236"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,21]]},"references-count":109,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms262010236"],"URL":"https:\/\/doi.org\/10.3390\/ijms262010236","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,21]]}}}