{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:16:25Z","timestamp":1788441385683,"version":"build-2803163510"},"reference-count":27,"publisher":"IMR Press","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hungarian University of Sports Science","award":["23-2026\/ HUSS_PUBL_FUND"],"award-info":[{"award-number":["23-2026\/ HUSS_PUBL_FUND"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Alzheimer\u2019s disease initiates pathophysiology in the 10 to 20 years prior to detectable clinical symptoms. A recent genetic analysis implicated the critical role of Piezo2 in Alzheimer\u2019s disease pathophysiology. A recent genetic study, involving PIEZO1 manipulation, showed that phosphatidylinositol 4,5-bisphosphate (PIP2) rectified brain capillary endothelial Piezo1 channelopathy in a mouse model of Alzheimer\u2019s disease. However, the present opinion paper posits that the initiating microdamage is in the prefrontal cortex, further upstream of pathophysiology, namely an irreversible Piezo2 channelopathy of glutamatergic terminals that is proposed to finely regulate oxytocin release resulting from stressful ultradian events, leading to impaired ultradian rhythm. The involvement of Piezo2 in the defensive arousal response reveals an underlying body-wide Piezo2 system of which the proposed prefrontal Piezo2 channelopathy is possibly a critical locus. PIP2 is emerging as a potential treatment method for Piezo channelopathy in Alzheimer\u2019s disease. However, the challenge of its more precise administration to target affected regions of the brain still remains.<\/jats:p>","DOI":"10.31083\/fbl52555","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:35:31Z","timestamp":1788438931000},"source":"Crossref","is-referenced-by-count":0,"title":["Alzheimer\u2019s Disease, Piezo2 Channelopathy, Piezo1 Channelopathy, and the Body-Wide Piezo2 System"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1267-1306","authenticated-orcid":true,"given":"Balazs","family":"Sonkodi","sequence":"first","affiliation":[{"name":"Department of Health Sciences and Sport Medicine, Hungarian University of Sports Science, 1123 Budapest, Hungary"},{"name":"Department of Sports Medicine, Semmelweis University, 1122 Budapest, Hungary"},{"name":"Faculty of Health Sciences, Institute of Physiotherapy and Sport Science, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"},{"name":"Physical Activity Research Group, Szent\u00e1gothai Research Centre, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Willett JDS, Waqas M, Naumenko S, Mullin K, Hecker J, Bertram L, et al. Matching heterogeneous cohorts by projected principal components reveals two novel Alzheimer's disease-associated genes in the Hispanic population. Alzheimer's & Dementia : the Journal of the Alzheimer's Association. 2026; 22: e71189.","DOI":"10.1002\/alz.71189"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Hashad AM, Abd-Alhaseeb MM, Lim XR, Mathieu NM, Harraz OF. PIP2 corrects an endothelial Piezo1 channelopathy. Proceedings of the National Academy of Sciences of the United States of America. 2025; 122: e2522750122.","DOI":"10.1073\/pnas.2522750122"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Sonkodi B, Kopa Z, Nyir\u00e1dy P. Post Orgasmic Illness Syndrome (POIS) and Delayed Onset Muscle Soreness (DOMS): Do They Have Anything in Common? Cells. 2021; 10: 1867.","DOI":"10.3390\/cells10081867"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Sonkodi B. Acquired Piezo2 Channelopathy is One Principal Gateway to Pathophysiology. Frontiers in Bioscience (Landmark Edition). 2025; 30: 33389.","DOI":"10.31083\/FBL33389"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Romero LO, Caires R, Kaitlyn Victor A, Ramirez J, Sierra-Valdez FJ, Walsh P, et al. Linoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome. Nature Communications. 2023; 14: 1167.","DOI":"10.1038\/s41467-023-36818-0"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Romero LO, Bade M, Carrillo E, Paz-L\u00f3pez S, Hasan SAM, Antonisamy WJ, et al. Cofilin Inhibition Ameliorates PIEZO2 and AMPA Dysfunction in a Mouse Model of Angelman Syndrome. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2025; 45: e0965252025.","DOI":"10.1523\/JNEUROSCI.0965-25.2025"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Sonkodi B, Nagy ZF, Keller-Pint\u00e9r A, Kliv\u00e9nyi P, Moln\u00e1r MJ, Sz\u00e9ll M. Genetic Variants in SDC3, KCNA2, KCNK1, KCNK16, and Heat Shock Transcription Factor-1 Genes: An Exploratory Analysis Supporting the Piezo2 Channelopathy Hypothesis in Amyotrophic Lateral Sclerosis Onset. International Journal of Molecular Sciences. 2025; 26: 10218.","DOI":"10.3390\/ijms262010218"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Sonkodi B, Resch MD, Hortob\u00e1gyi T. Is the Sex Difference a Clue to the Pathomechanism of Dry Eye Disease? Watch out for the NGF-TrkA-Piezo2 Signaling Axis and the Piezo2 Channelopathy. Journal of Molecular Neuroscience : MN. 2022; 72: 1598\u20131608.","DOI":"10.1007\/s12031-022-02015-9"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Sonkodi B. The Microbiota-Gut-Brain Axis in Light of the Brain Axes and Dysbiosis Where Piezo2 Is the Critical Initiating Player. International Journal of Molecular Sciences. 2025; 26: 7211.","DOI":"10.3390\/ijms26157211"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Kashani A, Lepicard E, Poirel O, Videau C, David JP, Fallet-Bianco C, et al. Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease. Neurobiology of Aging. 2008; 29: 1619\u20131630.","DOI":"10.1016\/j.neurobiolaging.2007.04.010"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Zhang Q, Ma H, Huo L, Wang S, Yang Q, Ye Z, et al. Neural mechanism of trigeminal nerve stimulation recovering defensive arousal responses in traumatic brain injury. Theranostics. 2025; 15: 2315\u20132337.","DOI":"10.7150\/thno.106323"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Bir\u00f3 L, Buday Z, K\u00f3ta K, L\u0151rincz S, Acs\u00e1dy L. Convergence and Segregation of Excitatory and Inhibitory Afferents in the Paraventricular Thalamic Nucleus. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2025; 45: e0539252025.","DOI":"10.1523\/JNEUROSCI.0539-25.2025"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Bush D, Bisby JA, Bird CM, Gollwitzer S, Rodionov R, Diehl B, et al. Human hippocampal theta power indicates movement onset and distance travelled. Proceedings of the National Academy of Sciences of the United States of America. 2017; 114: 12297\u201312302.","DOI":"10.1073\/pnas.1708716114"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Hamill OP. Piezo2 in Paraventricular Neurons: Linking Heartbeat Pulsatility to Increased Oxytocin Release and Social Behavior. Journal of Integrative Neuroscience. 2025; 24: 47856.","DOI":"10.31083\/JIN47856"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Selles MC, Fortuna JTS, de Faria YPR, Siqueira LD, Lima-Filho R, Longo BM, et al. Oxytocin attenuates microglial activation and restores social and non-social memory in APP\/PS1 Alzheimer model mice. iScience. 2023; 26: 106545.","DOI":"10.1016\/j.isci.2023.106545"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Kiani I, Mohseni G, Hassani T, Taghilou A, Saligheh Rad H, Aghamollaii V. Posterior cingulate cortex atrophy across the Alzheimer's disease spectrum: A cross-sectional MRI study linking volumetrics to cognitive decline. Journal of Alzheimer's Disease : JAD. 2026; 109: 972\u2013979.","DOI":"10.1177\/13872877251401612"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Goutagny R, Gu N, Cavanagh C, Jackson J, Chabot JG, Quirion R, et al. Alterations in hippocampal network oscillations and theta-gamma coupling arise before A\u03b2 overproduction in a mouse model of Alzheimer's disease. The European Journal of Neuroscience. 2013; 37: 1896\u20131902.","DOI":"10.1111\/ejn.12233"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Wirt RA, Crew LA, Ortiz AA, McNeela AM, Flores E, Kinney JW, et al. Altered theta rhythm and hippocampal-cortical interactions underlie working memory deficits in a hyperglycemia risk factor model of Alzheimer's disease. Communications Biology. 2021; 4: 1036.","DOI":"10.1038\/s42003-021-02558-4"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Sonkodi B. Delayed-Onset Muscle Soreness Begins with a Transient Neural Switch. International Journal of Molecular Sciences. 2025; 26: 2319.","DOI":"10.3390\/ijms26052319"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Valla J, Berndt JD, Gonzalez-Lima F. Energy hypometabolism in posterior cingulate cortex of Alzheimer's patients: superficial laminar cytochrome oxidase associated with disease duration. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2001; 21: 4923\u20134930.","DOI":"10.1523\/JNEUROSCI.21-13-04923.2001"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Stuve O, Weideman RA, McMahan DM, Jacob DA, Little BB. Diclofenac reduces the risk of Alzheimer's disease: a pilot analysis of NSAIDs in two US veteran populations. Therapeutic Advances in Neurological Disorders. 2020; 13: 1756286420935676.","DOI":"10.1177\/1756286420935676"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Sztacho M, \u010cervenka J, \u0160alovsk\u00e1 B, Antiga L, Hoboth P, Hoz\u00e1k P. The RNA-dependent association of phosphatidylinositol 4,5-bisphosphate with intrinsically disordered proteins contribute to nuclear compartmentalization. PLoS Genetics. 2024; 20: e1011462.","DOI":"10.1371\/journal.pgen.1011462"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Ding C, Leow MKS, Magkos F. Oxytocin in metabolic homeostasis: implications for obesity and diabetes management. Obesity Reviews : an Official Journal of the International Association for the Study of Obesity. 2019; 20: 22\u201340.","DOI":"10.1111\/obr.12757"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Simon C, Brandenberger G. Ultradian oscillations of insulin secretion in humans. Diabetes. 2002; 51: S258\u2013S261.","DOI":"10.2337\/diabetes.51.2007.s258"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"O'Meara NM, Sturis J, Van Cauter E, Polonsky KS. Lack of control by glucose of ultradian insulin secretory oscillations in impaired glucose tolerance and in non-insulin-dependent diabetes mellitus. The Journal of Clinical Investigation. 1993; 92: 262\u2013271.","DOI":"10.1172\/JCI116560"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Sturis J, Polonsky KS, Shapiro ET, Blackman JD, O'Meara NM, van Cauter E. Abnormalities in the ultradian oscillations of insulin secretion and glucose levels in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1992; 35: 681\u2013689.","DOI":"10.1007\/BF00400263"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Phan TX, Malkani RG. Sleep and circadian rhythm disruption and stress intersect in Alzheimer's disease. Neurobiology of Stress. 2018; 10: 100133.","DOI":"10.1016\/j.ynstr.2018.10.001"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/8\/10.31083\/FBL52555","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:37:05Z","timestamp":1788439025000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/8\/10.31083\/FBL52555"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":27,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026]]}},"alternative-id":["S2768-6701(26)02193-3"],"URL":"https:\/\/doi.org\/10.31083\/fbl52555","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,31]]},"article-number":"52555"}}