{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:13:33Z","timestamp":1760058813130,"version":"build-2065373602"},"reference-count":107,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute on Aging","award":["# 1RF1AG062479-01"],"award-info":[{"award-number":["# 1RF1AG062479-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Familial Alzheimer\u2019s disease (FAD) is a complex multifactorial disorder clinically characterized by cognitive impairment and memory loss. Pathologically, FAD is characterized by intracellular accumulation of the protein fragment A\u03b242 (iA\u03b2), hyperphosphorylated microtubule-associated protein TAU (p-TAU), and extensive degeneration of basal forebrain cholinergic neurons of the nucleus basalis of Meynert (NbM) and the medial septal nucleus (MSN), mainly caused by mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and PSEN2 gene. Since the dopaminergic system may contribute to FAD symptoms, alterations in the nigro-hippocampal pathway may be associated with cognitive impairment in FAD. Interestingly, p-\u03b1-synuclein (p-\u03b1-Syn), A\u03b2, and p-TAU have been found to coexist in vulnerable regions of postmortem AD brains. However, the mechanism by which A\u03b2, p-TAU, and \u03b1-Syn coexist in DAergic neurons in AD brains has not been determined. We generated PSEN1 I416T dopaminergic-like neurons (DALNs) from I416T menstrual stromal cells (MenSCs) in NeuroForsk 2.0 medium for 7 days and then cultured them in minimal culture medium (MCm) for another 4 days. On day 11, DALNs were analyzed for molecular and pathological markers by flow cytometry and fluorescence microscopy. We found that mutant DALNs showed increased accumulation of iA\u03b2 as well as increased phosphorylation of TAU at S202\/T205 compared to WT DALNs. Thus, mutant DALNs exhibited typical pathological hallmarks of Alzheimer\u2019s disease. Furthermore, PSEN1 I416T DALNs showed concomitant signs of OS as evidenced by the appearance of oxidized sensor protein DJ-1 (i.e., DJ-1C106-SO3) and apoptotic markers TP53, pS63-c-JUN, PUMA, and cleavage caspase 3 (CC3). Notably, these DALNs exhibited PD-associated proteins such as intracellular accumulation of \u03b1-Syn (detected as aggregates of pS129-\u03b1-Syn) and phosphorylation of LRRK2 kinase at residue S935. In addition, mutant DALNs showed a 17.16- and 6.17-fold decrease in DA-induced Ca2+ flux, compared to WT DALNs. These observations suggest that iA\u03b2 and p-TAU, together with p-\u03b1-Syn, and p-LRRK2 kinase, may damage DAergic neurons and thereby contribute to the exacerbation of neuropathologic processes in FAD. Remarkably, the LRRK2 inhibitor PF-06447475 (PF-475) significantly reversed PSEN1 I416T-induced neuropathological markers in DAergic neurons. PF-465 inhibitor reduced iA\u03b2, oxDJ-1C106-SO3, and p-TAU. In addition, this inhibitor reduced pS935-LRRK2, pS129-\u03b1SYN, pS63-c-JUN, and CC3. We conclude that the observed neuroprotective effects of PF-475 are due to direct inhibition of LRRK2 activity and that the LRRK2 protein is upstream of the molecular cascade of apoptosis and proteinopathy. Our results suggest that PF-475 is an effective neuroprotective agent against endogenous PSEN1 I416T-induced neurotoxicity in DALNs coexisting with Parkinson\u2019s disease markers. Therefore, PF-475 may be of great therapeutic value in FAD.<\/jats:p>","DOI":"10.3390\/molecules30092034","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T08:28:11Z","timestamp":1746174491000},"page":"2034","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PF-06447475 Molecule Attenuates the Neuropathology of Familial Alzheimer\u2019s and Coexistent Parkinson\u2019s Disease Markers in PSEN1 I416T Dopaminergic-like Neurons"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6437-8234","authenticated-orcid":false,"given":"Diana Alejandra","family":"Quintero-Espinosa","sequence":"first","affiliation":[{"name":"Neuroscience Research Group, Institute of Medical Research, Faculty of Medicine, University Research Headquarters, Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0557-0411","authenticated-orcid":false,"given":"Carlos","family":"Velez-Pardo","sequence":"additional","affiliation":[{"name":"Neuroscience Research Group, Institute of Medical Research, Faculty of Medicine, University Research Headquarters, Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3477-2386","authenticated-orcid":false,"given":"Marlene","family":"Jimenez-Del-Rio","sequence":"additional","affiliation":[{"name":"Neuroscience Research Group, Institute of Medical Research, Faculty of Medicine, University Research Headquarters, Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.clinbiochem.2019.04.015","article-title":"Clinical aspects of Alzheimer\u2019s disease","volume":"72","year":"2019","journal-title":"Clin. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s00401-015-1392-5","article-title":"Nucleus basalis of Meynert revisited: Anatomy, history and differential involvement in Alzheimer\u2019s and Parkinson\u2019s disease","volume":"129","author":"Liu","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kim, S., Nam, Y., Kim, H.S., Jung, H., Jeon, S.G., Hong, S.B., and Moon, M. (2022). Alteration of Neural Pathways and Its Implications in Alzheimer\u2019s Disease. Biomedicines, 10.","DOI":"10.3390\/biomedicines10040845"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2798","DOI":"10.1093\/brain\/aws211","article-title":"Neuropathological correlates of dopaminergic imaging in Alzheimer\u2019s disease and Lewy body dementias","volume":"135","author":"Colloby","year":"2012","journal-title":"Brain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.3233\/JAD-190954","article-title":"In vivo MRI Structural and PET Metabolic Connectivity Study of Dopamine Pathways in Alzheimer\u2019s Disease","volume":"75","author":"Iaccarino","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14727","DOI":"10.1038\/ncomms14727","article-title":"Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer\u2019s disease","volume":"8","author":"Nobili","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_7","first-page":"71","article-title":"The nigrostriatal DA pathway and Parkinson\u2019s disease","volume":"70","author":"Fuxe","year":"2006","journal-title":"J. Neural Transm. Suppl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA Research Framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref_9","first-page":"a006189","article-title":"Neuropathological alterations in Alzheimer disease","volume":"1","author":"Frosch","year":"2011","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_10","first-page":"415","article-title":"Tauopathy in basal ganglia involvement is exacerbated in a subset of patients with Alzheimer\u2019s disease: The Hisayama study","volume":"11","author":"Hamasaki","year":"2019","journal-title":"Alzheimers Dement."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13024-019-0329-1","article-title":"Alpha-synuclein structure and Parkinson\u2019s disease\u2014Lessons and emerging principles","volume":"14","author":"Meade","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13024-019-0320-x","article-title":"\u03b1-synuclein in the pathophysiology of Alzheimer\u2019s disease","volume":"14","author":"Twohig","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"King, A., Bodi, I., and Troakes, C. (2020). The Neuropathological Diagnosis of Alzheimer\u2019s Disease-The Challenges of Pathological Mimics and Concomitant Pathology. Brain Sci., 10.","DOI":"10.3390\/brainsci10080479"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.tins.2021.12.002","article-title":"LRRK2 and idiopathic Parkinson\u2019s disease","volume":"45","author":"Rocha","year":"2022","journal-title":"Trends Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/JAD-2012-120907","article-title":"Phenotypic profile of early-onset familial Alzheimer\u2019s disease caused by presenilin-1 E280A mutation","volume":"32","author":"Glatzel","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1002\/alz.12109","article-title":"Baseline demographic, clinical, and cognitive characteristics of the Alzheimer\u2019s Prevention Initiative (API) Autosomal-Dominant Alzheimer\u2019s Disease Colombia Trial","volume":"16","author":"Lopera","year":"2020","journal-title":"Alzheimers Dement."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wolfe, M.S., and Miao, Y. (2022). Structure and mechanism of the \u03b3-secretase intramembrane protease complex. Curr. Opin. Struct. Biol., 74.","DOI":"10.1016\/j.sbi.2022.102373"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Do, H.N., Devkota, S., Bhattarai, A., Wolfe, M.S., and Miao, Y. (2023). Effects of presenilin-1 familial Alzheimer\u2019s disease mutations on \u03b3-secretase activation for cleavage of amyloid precursor protein. Commun. Biol., 6.","DOI":"10.1038\/s42003-023-04539-1"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.jalz.2018.12.010","article-title":"Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr)","volume":"15","author":"Giraldo","year":"2019","journal-title":"Alzheimers Dement."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gomez-Sequeda, N., Mendivil-Perez, M., Jimenez-Del-Rio, M., Lopera, F., and Velez-Pardo, C. (2023). Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer\u2019s disease neuropathology. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-39630-4"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13024-019-0344-2","article-title":"LRRK2 Biology from structure to dysfunction: Research progresses, but the themes remain the same","volume":"14","author":"Berwick","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e00660-20","DOI":"10.1128\/MCB.00660-20","article-title":"The Cell Biology of LRRK2 in Parkinson\u2019s Disease","volume":"41","author":"Usmani","year":"2021","journal-title":"Mol. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s12640-024-00705-3","article-title":"Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson\u2019s Disease Dementia (PDD)","volume":"42","year":"2024","journal-title":"Neurotox. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.bbrc.2009.06.142","article-title":"Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications","volume":"387","author":"Qing","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.yexcr.2009.09.014","article-title":"LRRK2 enhances oxidative stress-induced neurotoxicity via its kinase activity","volume":"316","author":"Heo","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eadl3438","DOI":"10.1126\/scitranslmed.adl3438","article-title":"LRRK2 regulates production of reactive oxygen species in cell and animal models of Parkinson\u2019s disease","volume":"16","author":"Keeney","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.brainres.2016.12.023","article-title":"Knockdown transgenic Lrrk Drosophila resists paraquat-induced locomotor impairment and neurodegeneration: A therapeutic strategy for Parkinson\u2019s disease","volume":"1657","year":"2017","journal-title":"Brain Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Quintero-Espinosa, D.A., Sanchez-Hernandez, S., Velez-Pardo, C., Martin, F., and Jimenez-Del-Rio, M. (2023). LRRK2 Knockout Confers Resistance in HEK-293 Cells to Rotenone-Induced Oxidative Stress, Mitochondrial Damage, and Apoptosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310474"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1002\/tox.23433","article-title":"Phenolic-rich extract of avocado Persea americana (var. Colinred) peel blunts paraquat\/maneb-induced apoptosis through blocking phosphorylation of LRRK2 kinase in human nerve-like cells","volume":"37","year":"2022","journal-title":"Environ. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.ceb.2020.01.001","article-title":"Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson\u2019s disease","volume":"63","author":"Taylor","year":"2020","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"147394","DOI":"10.1016\/j.brainres.2021.147394","article-title":"LRRK2; a dynamic regulator of cellular trafficking","volume":"1761","author":"Follett","year":"2021","journal-title":"Brain Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ravinther, A.I., Dewadas, H.D., Tong, S.R., Foo, C.N., Lin, Y.-E., Chien, C.-T., and Lim, Y.M. (2022). Molecular Pathways Involved in LRRK2-Linked Parkinson\u2019s Disease: A Systematic Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911744"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1007\/s11064-016-1982-1","article-title":"Neuroprotective Effect of the LRRK2 Kinase Inhibitor PF-06447475 in Human Nerve-Like Differentiated Cells Exposed to Oxidative Stress Stimuli: Implications for Parkinson\u2019s Disease","volume":"41","year":"2016","journal-title":"Neurochem. Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ilieva, N.M., Hoffman, E.K., Ghalib, M.A., Greenamyre, J.T., and De Miranda, B.R. (2024). LRRK2 kinase inhibition protects against Parkinson\u2019s disease-associated environmental toxicants. Neurobiol. Dis., 196.","DOI":"10.1016\/j.nbd.2024.106522"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Quintero-Espinosa, D.A., Velez-Pardo, C., and Jimenez-Del-Rio, M. (2023). High Yield of Functional Dopamine-like Neurons Obtained in NeuroForsk 2.0 Medium to Study Acute and Chronic Rotenone Effects on Oxidative Stress, Autophagy, and Apoptosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115744"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.jneumeth.2017.03.005","article-title":"Fast transdifferentiation of human Wharton\u2019s jelly mesenchymal stem cells into neurospheres and nerve-like cells","volume":"282","year":"2017","journal-title":"J. Neurosci. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1021\/jm5014055","article-title":"Discovery and Preclinical Profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase Inhibitor","volume":"58","author":"Henderson","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.abb.2010.12.017","article-title":"Tyrosine hydroxylase and regulation of dopamine synthesis","volume":"508","author":"Daubner","year":"2011","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Nepal, B., Das, S., Reith, M.E., and Kortagere, S. (2023). Overview of the structure and function of the dopamine transporter and its protein interactions. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1150355"},{"key":"ref_40","first-page":"201","article-title":"Forskolin: A unique diterpene activator of cyclic AMP-generating systems","volume":"7","author":"Seamon","year":"1981","journal-title":"J. Cycl. Nucleotide Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Thompson, R., Casali, C., and Chan, C. (2019). Forskolin and IBMX Induce Neural Transdifferentiation of MSCs Through Downregulation of the NRSF. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-39544-0"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"31","DOI":"10.4103\/1673-5374.313016","article-title":"Presenilin mutations and their impact on neuronal differentiation in Alzheimer\u2019s disease","volume":"17","author":"Cevallos","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/B978-0-12-802395-2.00036-5","article-title":"Comorbidities","volume":"145","author":"Alafuzoff","year":"2017","journal-title":"Handb. Clin. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.nicl.2014.11.015","article-title":"Basal forebrain atrophy correlates with amyloid \u03b2 burden in Alzheimer\u2019s disease","volume":"7","author":"Kerbler","year":"2015","journal-title":"Neuroimage Clin."},{"key":"ref_45","first-page":"1","article-title":"[Neuropathological findings in early-onset Alzheimer\u2019s disease (E280a-PS1 mutation)]","volume":"29","author":"Cubillo","year":"1999","journal-title":"Rev. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/S1474-4422(12)70227-2","article-title":"Florbetapir PET analysis of amyloid-\u03b2 deposition in the presenilin 1 E280A autosomal dominant Alzheimer\u2019s disease kindred: A cross-sectional study","volume":"11","author":"Fleisher","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"102749","DOI":"10.1016\/j.nicl.2021.102749","article-title":"PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer\u2019s disease-causing Presenilin-1 E280A mutation carriers","volume":"31","author":"Ghisays","year":"2021","journal-title":"NeuroImage: Clin."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"174","DOI":"10.4103\/NRR.NRR-D-23-01781","article-title":"Emerging structures and dynamic mechanisms of \u03b3-secretase for Alzheimer\u2019s disease","volume":"20","author":"Miao","year":"2025","journal-title":"Neural Regen. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"E476","DOI":"10.1073\/pnas.1618657114","article-title":"Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of A\u03b242 and A\u03b240 peptides by \u03b3-secretase","volume":"114","author":"Sun","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/sj.embor.7400897","article-title":"Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease","volume":"8","year":"2007","journal-title":"EMBO Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.neuron.2015.02.010","article-title":"Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer\u2019s disease","volume":"85","author":"Xia","year":"2015","journal-title":"Neuron"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"12731","DOI":"10.1073\/pnas.1713605114","article-title":"Dominant negative effect of the loss-of-function \u03b3-secretase mutants on the wild-type enzyme through heterooligomerization","volume":"114","author":"Zhou","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.ijbiomac.2022.01.117","article-title":"Amyloid \u03b2 interaction with model cell membranes\u2014What are the toxicity-defining properties of amyloid \u03b2?","volume":"200","author":"Mrdenovic","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Novoa, C., Salazar, P., Cisternas, P., Gherardelli, C., Vera-Salazar, R., Zolezzi, J.M., and Inestrosa, N.C. (2022). Inflammation context in Alzheimer\u2019s disease, a relationship intricate to define. Biol. Res., 55.","DOI":"10.1186\/s40659-022-00404-3"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e2309389120","DOI":"10.1073\/pnas.2309389120","article-title":"A possible mechanism for the enhanced toxicity of beta-amyloid protofibrils in Alzheimer\u2019s disease","volume":"120","author":"Chen","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Gallego Villarejo, L., Bachmann, L., Marks, D., Brachth\u00e4user, M., Geidies, A., and M\u00fcller, T. (2022). Role of Intracellular Amyloid \u03b2 as Pathway Modulator, Biomarker, and Therapy Target. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094656"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"21","DOI":"10.3233\/ADR-220079","article-title":"The Amyloid Cascade Hypothesis 2.0: Generalization of the Concept","volume":"7","author":"Volloch","year":"2023","journal-title":"J. Alzheimers Dis. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"198430","DOI":"10.4061\/2011\/198430","article-title":"Methionine-35 of a\u03b2(1-42): Importance for oxidative stress in Alzheimer disease","volume":"2011","author":"Butterfield","year":"2011","journal-title":"J. Amino Acids"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.bbadis.2013.09.015","article-title":"Abeta, oxidative stress in Alzheimer disease: Evidence based on proteomics studies","volume":"1842","author":"Swomley","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_60","first-page":"94","article-title":"Effect of methionine-35 oxidation on the aggregation of amyloid-\u03b2 peptide","volume":"3","author":"Friedemann","year":"2015","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1111\/bph.14585","article-title":"Mitochondrial dysfunction in Alzheimer\u2019s disease: Role in pathogenesis and novel therapeutic opportunities","volume":"176","author":"Swerdlow","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Sinclair, P., Baranova, A., and Kabbani, N. (2021). Mitochondrial Disruption by Amyloid Beta 42 Identified by Proteomics and Pathway Mapping. Cells, 10.","DOI":"10.3390\/cells10092380"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Meng, X., Song, Q., Liu, Z., Liu, X., Wang, Y., and Liu, J. (2024). Neurotoxic \u03b2-amyloid oligomers cause mitochondrial dysfunction-the trigger for PANoptosis in neurons. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1400544"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Atlante, A., and Valenti, D. (2023). Mitochondrial Complex I and \u03b2-Amyloid Peptide Interplay in Alzheimer\u2019s Disease: A Critical Review of New and Old Little Regarded Findings. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115951"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.mito.2013.03.008","article-title":"Mitochondrial respiratory chain Complexes I and IV are impaired by \u03b2-amyloid via direct interaction and through Complex I-dependent ROS production, respectively","volume":"13","author":"Bobba","year":"2013","journal-title":"Mitochondrion"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.redox.2015.02.001","article-title":"Teaching the fundamentals of electron transfer reactions in mitochondria and the production and detection of reactive oxygen species","volume":"4","author":"Mailloux","year":"2015","journal-title":"Redox Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.bbrc.2004.03.110","article-title":"Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxide-mediated oxidation in vivo in human umbilical vein endothelial cells","volume":"317","author":"Kinumi","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3164\/jcbn.13-108","article-title":"Oxidized DJ-1 as a possible biomarker of Parkinson\u2019s disease","volume":"54","author":"Saito","year":"2014","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Mita, Y., Kataoka, Y., Saito, Y., Kashi, T., Hayashi, K., Iwasaki, A., Imanishi, T., Miyasaka, T., and Noguchi, N. (2018). Distribution of oxidized DJ-1 in Parkinson\u2019s disease-related sites in the brain and in the peripheral tissues: Effects of aging and a neurotoxin. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-30561-z"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"10963","DOI":"10.1021\/bi9011379","article-title":"Identification of the autophosphorylation sites of LRRK2","volume":"48","author":"Kamikawaji","year":"2009","journal-title":"Biochemistry"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1093\/hmg\/ddl471","article-title":"Parkinson\u2019s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity","volume":"16","author":"West","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1523\/JNEUROSCI.5604-09.2010","article-title":"Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson\u2019s disease mutation G2019S","volume":"30","author":"Li","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"29569","DOI":"10.1074\/jbc.M110.127639","article-title":"Reevaluation of phosphorylation sites in the Parkinson disease-associated leucine-rich repeat kinase 2","volume":"285","author":"Li","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Dzamko, N., Inesta-Vaquera, F., Zhang, J., Xie, C., Cai, H., Arthur, S., Tan, L., Choi, H., Gray, N., and Cohen, P. (2012). The IkappaB kinase family phosphorylates the Parkinson\u2019s disease kinase LRRK2 at Ser935 and Ser910 during Toll-like receptor signaling. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039132"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1093\/hmg\/dds003","article-title":"LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1","volume":"21","author":"Wang","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1002\/humu.21582","article-title":"Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death","volume":"32","author":"Angeles","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.1016\/j.bbamcr.2017.09.001","article-title":"LRRK2 functions as a scaffolding kinase of ASK1-mediated neuronal cell death","volume":"1864","author":"Yoon","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1038\/cdd.2012.42","article-title":"(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD","volume":"19","author":"Chen","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13041-015-0145-7","article-title":"Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21(WAF1\/CIP1) expression","volume":"8","author":"Ho","year":"2015","journal-title":"Mol. Brain"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/ncb748","article-title":"alpha-Synuclein is phosphorylated in synucleinopathy lesions","volume":"4","author":"Fujiwara","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1046\/j.1471-4159.2000.0741587.x","article-title":"Phosphorylation sites on tau identified by nanoelectrospray mass spectrometry: Differences in vitro between the mitogen-activated protein kinases ERK2, c-Jun N-terminal kinase and P38, and glycogen synthase kinase-3beta","volume":"74","author":"Reynolds","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_82","first-page":"1524","article-title":"JNK Activation in Alzheimer\u2019s Disease Is Driven by Amyloid \u03b2 and Is Associated with Tau Pathology","volume":"14","author":"Solas","year":"2023","journal-title":"ACS Chem. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3233\/JAD-131289","article-title":"Neuropathology of parkinsonism in patients with pure Alzheimer\u2019s disease","volume":"39","author":"Horvath","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s40478-019-0836-x","article-title":"Alzheimer\u2019s disease tau is a prominent pathology in LRRK2 Parkinson\u2019s disease","volume":"7","author":"Henderson","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s10495-023-01848-y","article-title":"Apoptosis in Alzheimer\u2019s disease: Insight into the signaling pathways and therapeutic avenues","volume":"28","author":"Kumari","year":"2023","journal-title":"Apoptosis"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Pedr\u00e3o, L., Medeiros, P.O.S., Leandro, E.C., and Falquetto, B. (2024). Parkinson\u2019s disease models and death signaling: What do we know until now?. Front. Neuroanat., 18.","DOI":"10.3389\/fnana.2024.1419108"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S1097-2765(01)00214-3","article-title":"PUMA, a novel proapoptotic gene, is induced by p53","volume":"7","author":"Nakano","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S1097-2765(01)00213-1","article-title":"PUMA induces the rapid apoptosis of colorectal cancer cells","volume":"7","author":"Yu","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.3892\/mmr.2014.1981","article-title":"c-Jun transactivates Puma gene expression to promote osteoarthritis","volume":"9","author":"Lu","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Roufayel, R., Younes, K., Al-Sabi, A., and Murshid, N. (2022). BH3-Only Proteins Noxa and Puma Are Key Regulators of Induced Apoptosis. Life, 12.","DOI":"10.3390\/life12020256"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"9357","DOI":"10.1074\/jbc.273.16.9357","article-title":"Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis","volume":"273","author":"Sprengart","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/2051-5960-2-16","article-title":"Caspase-mediated cleavage of actin and tubulin is a common feature and sensitive marker of axonal degeneration in neural development and injury","volume":"2","author":"Sokolowski","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41420-019-0142-1","article-title":"The prodomain of caspase-3 regulates its own removal and caspase activation","volume":"5","author":"Ponder","year":"2019","journal-title":"Cell Death Discov."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1046\/j.1471-4159.2000.0751155.x","article-title":"Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors","volume":"75","author":"Wang","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"5626","DOI":"10.1074\/jbc.275.8.5626","article-title":"beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer\u2019s disease pathology","volume":"275","author":"Wang","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"384","DOI":"10.2174\/1871527322666230627123426","article-title":"Role of Alpha-7-Nicotinic Acetylcholine Receptor in Alzheimer\u2019s Disease","volume":"23","author":"Singh","year":"2024","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1093\/brain\/awu131","article-title":"Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons","volume":"137","author":"Dragicevic","year":"2014","journal-title":"Brain"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.neuron.2014.03.016","article-title":"Neuronal voltage-gated calcium channels: Structure, function, and dysfunction","volume":"82","author":"Simms","year":"2014","journal-title":"Neuron"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.4103\/NRR.NRR-D-24-00230","article-title":"The dopaminergic system and Alzheimer\u2019s disease","volume":"20","author":"Zhang","year":"2025","journal-title":"Neural Regen. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1007\/s11064-024-04141-9","article-title":"LRRK2 Kinase Inhibitor PF-06447475 Protects Drosophila melanogaster against Paraquat-Induced Locomotor Impairment, Life Span Reduction, and Oxidative Stress","volume":"49","year":"2024","journal-title":"Neurochem. Res."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Kim, J., Pajarillo, E., Rizor, A., Son, D.S., Lee, J., Aschner, M., and Lee, E. (2019). LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210248"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s40035-024-00403-2","article-title":"LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression","volume":"13","author":"Lubben","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.bcp.2009.10.020","article-title":"Characterization of endogenous calcium responses in neuronal cell lines","volume":"79","author":"Vetter","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.heares.2009.05.006","article-title":"Cytoplasmic Ca(2+) concentration changes evoked by cholinergic stimulation in primary astrocyte cultures prepared from the rat cochlear nucleus","volume":"255","author":"Pap","year":"2009","journal-title":"Hear. Res."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Lazic, S.E., Clarke-Williams, C.J., and Munaf\u00f2, M.R. (2018). What exactly is \u2018N\u2019 in cell culture and animal experiments?. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2005282"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Madureira, M., Connor-Robson, N., and Wade-Martins, R. (2020). \u201cLRRK2: Autophagy and Lysosomal Activity\u201d. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00498"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/9\/2034\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:26:30Z","timestamp":1760030790000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/9\/2034"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,2]]},"references-count":107,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["molecules30092034"],"URL":"https:\/\/doi.org\/10.3390\/molecules30092034","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2025,5,2]]}}}