{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T12:55:33Z","timestamp":1782305733444,"version":"3.54.5"},"reference-count":144,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>This review examines a small interfering RNA (siRNA) designed for intrathecal (IT) injection, which reduces the formation of amyloid beta precursor protein (APP), a critical factor in the pathology of Alzheimer\u2019s disease (AD). The siRNA, designated ALN-APP, incorporates a 16-carbon chain (C16-siRNA) to enhance its delivery to the central nervous system (CNS) while leveraging advancements in specificity and duration of action based on previously approved drugs by the Food and Drug Administration. The development of ALN-APP involved a comprehensive analysis of the optimal carbon chain length and its conjugation position to the siRNA. Preclinical studies conducted on male Sprague Dawley rats, mice, and non-human primates (NHPs) demonstrated the efficacy of ALN-APP. In rats, an IT injection of C16-siRNAs at a concentration of 30 mg\/mL, delivering a dose of 0.9 mg, resulted in cranial distribution via cerebrospinal fluid and led to a 75% reduction in copper-zinc superoxide dismutase 1 (SOD1) mRNA levels. These effects were dose-dependent and persisted for three months across multiple brain regions. Furthermore, studies in NHPs indicated that soluble APP levels were reduced to below 25%, sustained for two months. In the cerebrovascular amyloid Nos2\u2212\/\u2212 (CVN) mouse model of AD, administration of 120 \u00b5g of siRNA via the intracerebroventricular route produced reductions in APP expression, with mRNA levels remaining suppressed for 60 days in the ventral cortex. Indeed, ALN-APP controlled neuropathology in 5xFAD mice by significantly reducing amyloid levels and brain neuroinflammation, with improved behaviors in the elevated plus maze. Following these promising results in animal models, ALN-APP advanced to a Phase 1 trial, designated ALN-APP-001, which assessed its safety and efficacy in 12 participants with early-onset Alzheimer\u2019s disease (EOAD). Initial findings revealed a 55% reduction in soluble APP\u03b1 and a 69% reduction in APP\u03b2 by day 15. These exploratory findings require further validation with larger cohorts and proper statistical analysis. In a subsequent cohort of 36 patients, administration of the 75 mg dose via IT injection led to mean reductions of 61.3% in soluble APP\u03b1 (sAPP\u03b1) and 73.5% in soluble APP\u03b2 (sAPP\u03b2) after one month. These silencing effects persisted for six months and were associated with important decreases in A\u03b242 and A\u03b240 levels. These results highlight the potential of ALN-APPs to address Alzheimer\u2019s pathology while maintaining a favorable safety profile. Whether ALN-APP succeeds in further clinical trials, key challenges include ensuring accessibility and affordability due to treatment costs, the need for specialized intrathecal administration, and establishing infrastructure for large-scale production of siRNAs. In conclusion, advancements in ALN-APP represent a promising strategy to reduce beta-amyloid formation in AD, with substantial biomarker reductions suggesting potential disease-modifying effects. Continued development may pave the way for innovative treatments for neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/ph19010026","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T16:19:26Z","timestamp":1766420366000},"page":"26","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["C16-siRNAs in Focus: Development of ALN-APP, a Promising RNAi-Based Therapeutic for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5019-4742","authenticated-orcid":false,"given":"Ricardo","family":"Titze-de-Almeida","sequence":"first","affiliation":[{"name":"Technology for Gene Therapy Laboratory, ASS 128, ICC Sul, University of Bras\u00edlia, Campus Darcy Ribeiro, FAV, Bras\u00edlia 70910-900, DF, Brazil"},{"name":"Research Center for Major Themes\u2014Neurodegenerative Disorders Division, University of Bras\u00edlia, Bras\u00edlia 70910-900, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme de Melo","family":"Oliveira Gomes","sequence":"additional","affiliation":[{"name":"Technology for Gene Therapy Laboratory, ASS 128, ICC Sul, University of Bras\u00edlia, Campus Darcy Ribeiro, FAV, Bras\u00edlia 70910-900, DF, Brazil"},{"name":"Research Center for Major Themes\u2014Neurodegenerative Disorders Division, University of Bras\u00edlia, Bras\u00edlia 70910-900, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9070-4695","authenticated-orcid":false,"given":"Tayn\u00e1 Cristina dos","family":"Santos","sequence":"additional","affiliation":[{"name":"Technology for Gene Therapy Laboratory, ASS 128, ICC Sul, University of Bras\u00edlia, Campus Darcy Ribeiro, FAV, Bras\u00edlia 70910-900, DF, Brazil"},{"name":"Research Center for Major Themes\u2014Neurodegenerative Disorders Division, University of Bras\u00edlia, Bras\u00edlia 70910-900, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6122-054X","authenticated-orcid":false,"given":"Simoneide Souza","family":"Titze-de-Almeida","sequence":"additional","affiliation":[{"name":"Technology for Gene Therapy Laboratory, ASS 128, ICC Sul, University of Bras\u00edlia, Campus Darcy Ribeiro, FAV, Bras\u00edlia 70910-900, DF, Brazil"},{"name":"Research Center for Major Themes\u2014Neurodegenerative Disorders Division, University of Bras\u00edlia, Bras\u00edlia 70910-900, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer Disease","volume":"7","author":"Knopman","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the Global Prevalence of Dementia in 2019 and Forecasted Prevalence in 2050: An Analysis for the Global Burden of Disease Study 2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Madnani, R.S. (2023). Alzheimer\u2019s Disease: A Mini-Review for the Clinician. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1178588"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/S1474-4422(21)00066-1","article-title":"Clinical Diagnosis of Alzheimer\u2019s Disease: Recommendations of the International Working Group","volume":"20","author":"Dubois","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.neuron.2020.02.034","article-title":"Alzheimer\u2019s Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways","volume":"106","author":"Zhao","year":"2020","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S165","DOI":"10.3233\/JAD-240658","article-title":"A Brief History of the Progress in Our Understanding of Genetics and Lifestyle, Especially Diet, in the Risk of Alzheimer\u2019s Disease","volume":"100","author":"Grant","year":"2024","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Nordestgaard, L.T., Christoffersen, M., and Frikke-Schmidt, R. (2022). Shared Risk Factors between Dementia and Atherosclerotic Cardiovascular Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179777"},{"key":"ref_8","first-page":"1284","article-title":"Meta-Analysis of Modifiable Risk Factors for Alzheimer\u2019s Disease","volume":"86","author":"Xu","year":"2015","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/jnnp-2014-310095","article-title":"Risk Factors for Predicting Progression from Mild Cognitive Impairment to Alzheimer\u2019s Disease: A Systematic Review and Meta-Analysis of Cohort Studies","volume":"87","author":"Li","year":"2016","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1212\/WNL.0000000000005303","article-title":"Resistance vs Resilience to Alzheimer Disease","volume":"90","author":"Vemuri","year":"2018","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41588-019-0358-2","article-title":"Genetic Meta-Analysis of Diagnosed Alzheimer\u2019s Disease Identifies New Risk Loci and Implicates A\u03b2, Tau, Immunity and Lipid Processing","volume":"51","author":"Kunkle","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1097\/WAD.0000000000000179","article-title":"Genetic Comparison of Symptomatic and Asymptomatic Persons with Alzheimer Disease Neuropathology","volume":"31","author":"Monsell","year":"2017","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Prpar Mihevc, S., and Majdi\u010d, G. (2019). Canine Cognitive Dysfunction and Alzheimer\u2019s Disease\u2014Two Facets of the Same Disease?. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00604"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s12035-020-02140-9","article-title":"Plasma Amyloid Beta Concentrations in Aged and Cognitively Impaired Pet Dogs","volume":"58","author":"Panek","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"re1","DOI":"10.1126\/sageke.2006.6.re1","article-title":"The Development of Amyloid \u03b2 Protein Deposits in the Aged Brain","volume":"2006","author":"Thal","year":"2006","journal-title":"Sci. Aging Knowl. Environ."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jalz.2011.10.007","article-title":"National Institute on Aging\u2013Alzheimer\u2019s Association Guidelines for the Neuropathologic Assessment of Alzheimer\u2019s Disease","volume":"8","author":"Hyman","year":"2012","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-011-0910-3","article-title":"National Institute on Aging\u2013Alzheimer\u2019s Association Guidelines for the Neuropathologic Assessment of Alzheimer\u2019s Disease: A Practical Approach","volume":"123","author":"Montine","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s13311-021-01146-y","article-title":"Neuropathology of Alzheimer\u2019s Disease","volume":"19","author":"Yachnis","year":"2022","journal-title":"Neurotherapeutics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13024-019-0333-5","article-title":"The Neuropathological Diagnosis of Alzheimer\u2019s Disease","volume":"14","author":"DeTure","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/0197-4580(93)90038-D","article-title":"\u03b2-Amyloid Accumulation in Aged Canine Brain: A Model of Early Plaque Formation in Alzheimer\u2019s Disease","volume":"14","author":"Cummings","year":"1993","journal-title":"Neurobiol. Aging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.neurobiolaging.2005.02.017","article-title":"A Comparison of Immunohistochemical and Silver Staining Methods for the Detection of Diffuse Plaques in the Aged Canine Brain","volume":"27","author":"Czasch","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"305","DOI":"10.3233\/JAD-2009-1050","article-title":"Association of Cardiovascular Factors and Alzheimer\u2019s Disease Plasma Amyloid-\u03b2 Protein in Subjective Memory Complainers","volume":"17","author":"Bates","year":"2009","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E1807","DOI":"10.1073\/pnas.1220484110","article-title":"ApoE Influences Amyloid-\u03b2 (A\u03b2) Clearance despite Minimal ApoE\/A\u03b2 Association in Physiological Conditions","volume":"110","author":"Verghese","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1111\/jnc.12202","article-title":"Alzheimer\u2019s A\u03b242 and A\u03b240 Peptides Form Interlaced Amyloid Fibrils","volume":"126","author":"Gu","year":"2013","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/psc.2789","article-title":"A\u03b242 and A\u03b240: Similarities and Differences","volume":"21","author":"Qiu","year":"2015","journal-title":"J. Pept. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","article-title":"Genome-Wide Meta-Analysis Identifies New Loci and Functional Pathways Influencing Alzheimer\u2019s Disease Risk","volume":"51","author":"Jansen","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/s41593-022-01084-8","article-title":"Faulty Autolysosome Acidification in Alzheimer\u2019s Disease Mouse Models Induces Autophagic Build-up of A\u03b2 in Neurons, Yielding Senile Plaques","volume":"25","author":"Lee","year":"2022","journal-title":"Nat. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.neuron.2020.01.018","article-title":"The Journey of the Synaptic Autophagosome: A Cell Biological Perspective","volume":"105","year":"2020","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1093\/jnen\/64.2.113","article-title":"Extensive Involvement of Autophagy in Alzheimer Disease: An Immuno-Electron Microscopy Study","volume":"64","author":"Nixon","year":"2005","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1016\/j.celrep.2015.07.050","article-title":"Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating VATPase-Mediated Lysosome Acidification","volume":"12","author":"Lee","year":"2015","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Fernandes, S.M., Mayer, J., Nilsson, P., and Shimozawa, M. (2025). How Close Is Autophagy-Targeting Therapy for Alzheimer\u2019s Disease to Clinical Use? A Summary of Autophagy Modulators in Clinical Studies. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1520949"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15430","DOI":"10.1007\/s12035-025-05216-6","article-title":"Deciphering Molecular and Signaling Pathways of Extracellular Vesicles-Based Therapeutics for Alzheimer\u2019s Disease","volume":"62","author":"Dhapola","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_33","first-page":"2190","article-title":"The Autophagy-Related Protein Beclin 1 Shows Reduced Expression in Early Alzheimer Disease and Regulates Amyloid \u03b2 Accumulation in Mice","volume":"118","author":"Pickford","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Chen, S.Y., Gao, Y., Sun, J.Y., Meng, X.L., Yang, D., Fan, L.H., Xiang, L., and Wang, P. (2020). Traditional Chinese Medicine: Role in Reducing \u03b2-Amyloid, Apoptosis, Autophagy, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction of Alzheimer\u2019s Disease. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00497"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e21776","DOI":"10.7554\/eLife.21776","article-title":"Impaired Retrograde Transport of Axonal Autophagosomes Contributes to Autophagic Stress in Alzheimer\u2019s Disease Neurons","volume":"6","author":"Tammineni","year":"2017","journal-title":"eLife"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1212\/WNL.0000000000001401","article-title":"Spatially Distinct Atrophy Is Linked to \u03b2-Amyloid and Tau in Preclinical Alzheimer Disease","volume":"84","author":"Wang","year":"2015","journal-title":"Neurology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"652","DOI":"10.14336\/AD.2022.0927","article-title":"Novel Insight into Functions of Transcription Factor EB (TFEB) in Alzheimer\u2019s Disease and Parkinson\u2019s Disease","volume":"14","author":"Yang","year":"2023","journal-title":"Aging Dis."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Bagaria, J., Bagyinszky, E., and An, S.S.A. (2022). Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810970"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s10571-016-0386-8","article-title":"Autophagy and Alzheimer\u2019s Disease","volume":"37","author":"Li","year":"2017","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41392-024-01911-3","article-title":"Recent Advances in Alzheimer\u2019s Disease: Mechanisms, Clinical Trials and New Drug Development Strategies","volume":"9","author":"Zhang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1179573520907397","DOI":"10.1177\/1179573520907397","article-title":"Current and Future Treatments in Alzheimer Disease: An Update","volume":"12","author":"Yiannopoulou","year":"2020","journal-title":"J. Cent. Nerv. Syst. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer\u2019s Disease: Causes and Treatment. Molecules, 25.","DOI":"10.3390\/molecules25245789"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3233\/JAD-220046","article-title":"Safety and Efficacy of Monoclonal Antibodies for Alzheimer\u2019s Disease: A Systematic Review and Meta-Analysis of Published and Unpublished Clinical Trials","volume":"87","author":"Lacorte","year":"2022","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1212\/WNL.0000000000207757","article-title":"Antiamyloid Monoclonal Antibody Therapy for Alzheimer Disease: Emerging Issues in Neurology","volume":"101","author":"Ramanan","year":"2023","journal-title":"Neurology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s40259-023-00633-2","article-title":"Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer\u2019s Disease","volume":"38","author":"Cummings","year":"2024","journal-title":"BioDrugs"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/nature02873","article-title":"Mechanisms of Gene Silencing by Double-Stranded RNA","volume":"431","author":"Meister","year":"2004","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/35888","article-title":"Potent and Specific Genetic Interference by Double-Stranded RNA in Caenorhabditis Elegans","volume":"391","author":"Fire","year":"1998","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1007\/s11095-017-2134-2","article-title":"The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market","volume":"34","author":"David","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1146\/annurev-biophys-083012-130404","article-title":"Molecular Mechanisms of RNA Interference","volume":"42","author":"Wilson","year":"2013","journal-title":"Annu. Rev. Biophys."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.cell.2009.01.035","article-title":"Origins and Mechanisms of MiRNAs and SiRNAs","volume":"136","author":"Carthew","year":"2009","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1146\/annurev.cellbio.23.090506.123406","article-title":"MicroRNA Functions","volume":"23","author":"Bushati","year":"2007","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1016\/j.febslet.2014.05.030","article-title":"Renaissance of Mammalian Endogenous RNAi","volume":"588","author":"Svoboda","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.devcel.2011.01.012","article-title":"The Many Faces of RNAi","volume":"20","author":"Ketting","year":"2011","journal-title":"Dev. Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"17897","DOI":"10.1074\/jbc.R900012200","article-title":"The RNA-Induced Silencing Complex: A Versatile Gene-Silencing Machine","volume":"284","author":"Pratt","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/nature07755","article-title":"A Three-Dimensional View of the Molecular Machinery of RNA Interference","volume":"457","author":"Jinek","year":"2009","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.cell.2006.12.001","article-title":"RNA Interference: Big Applause for Silencing in Stockholm","volume":"127","author":"Zamore","year":"2007","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0092-8674(00)80620-0","article-title":"RNAi: Double-Stranded RNA Directs the ATP-Dependent Cleavage of MRNA at 21 to 23 Nucleotide Intervals","volume":"101","author":"Zamore","year":"2000","journal-title":"Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s40259-022-00549-3","article-title":"Therapeutic siRNA: State-of-the-Art and Future Perspectives","volume":"36","author":"Friedrich","year":"2022","journal-title":"BioDrugs"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1146\/annurev-pharmtox-010818-021050","article-title":"Therapeutic Oligonucleotides: State of the Art","volume":"59","author":"Smith","year":"2019","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1097\/WCO.0000000000000289","article-title":"First European Consensus for Diagnosis, Management, and Treatment of Transthyretin Familial Amyloid Polyneuropathy","volume":"29","author":"Adams","year":"2016","journal-title":"Curr. Opin. Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/d41586-018-05867-7","article-title":"Gene-Silencing Technology Gets First Drug Approval after 20-Year Wait","volume":"560","author":"Ledford","year":"2018","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1089\/nat.2017.0715","article-title":"Journey of SiRNA: Clinical Developments and Targeted Delivery","volume":"28","author":"Nikam","year":"2018","journal-title":"Nucleic Acid. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s40291-019-00438-6","article-title":"Leading RNA Interference Therapeutics Part 2: Silencing Delta-Aminolevulinic Acid Synthase 1, with a Focus on Givosiran","volume":"24","year":"2020","journal-title":"Mol. Diagn. Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1016\/j.ymthe.2017.03.013","article-title":"Lipid Nanoparticle Systems for Enabling Gene Therapies","volume":"25","author":"Cullis","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1089\/nat.2018.0721","article-title":"Lipid Nanoparticles Enabling Gene Therapies: From Concepts to Clinical Utility","volume":"28","author":"Kulkarni","year":"2018","journal-title":"Nucleic Acid. Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1716153","article-title":"Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis","volume":"379","author":"Adams","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5","DOI":"10.2217\/nmt-2018-0033","article-title":"Patisiran, an RNAi Therapeutic for the Treatment of Hereditary Transthyretin-Mediated Amyloidosis","volume":"9","author":"Kristen","year":"2019","journal-title":"Neurodegener. Dis. Manag."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s40291-019-00434-w","article-title":"Leading RNA Interference Therapeutics Part 1: Silencing Hereditary Transthyretin Amyloidosis, with a Focus on Patisiran","volume":"24","author":"Faber","year":"2020","journal-title":"Mol. Diagn. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/jcph.2337","article-title":"Pharmacokinetics and Pharmacodynamics of GalNAc-Conjugated SiRNAs","volume":"64","author":"An","year":"2024","journal-title":"J. Clin. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"16958","DOI":"10.1021\/ja505986a","article-title":"Multivalent N-Acetylgalactosamine-Conjugated SiRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing","volume":"136","author":"Nair","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ymthe.2017.08.019","article-title":"Evaluation of GalNAc-SiRNA Conjugate Activity in Pre-Clinical Animal Models with Reduced Asialoglycoprotein Receptor Expression","volume":"26","author":"Willoughby","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1038\/s41587-022-01334-x","article-title":"Expanding RNAi Therapeutics to Extrahepatic Tissues with Lipophilic Conjugates","volume":"40","author":"Brown","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4382","DOI":"10.1093\/nar\/gkaa164","article-title":"Mechanisms of Palmitic Acid-Conjugated Antisense Oligonucleotide Distribution in Mice","volume":"48","author":"Chappell","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_74","unstructured":"Jadhav, V., and Maier, M. (2025, July 05). Expanding the Reach of RNAi Therapeutics with Next Generation Lipophilic SiRNA Conjugates. Available online: https:\/\/communities.springernature.com\/posts\/expanding-the-reach-of-rnai-therapeutics-with-next-generation-lipophilic-sirna-conjugates."},{"key":"ref_75","unstructured":"Alnylam Pharmaceutics, Inc. (2025, July 05). Alnylam. Delivery Platforms\u2014C16 Conjugates. Available online: https:\/\/www.alnylam.com\/our-science\/sirna-delivery-platforms."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"102357","DOI":"10.1016\/j.arr.2024.102357","article-title":"Neurodegenerative Disorders: Mechanisms of Degeneration and Therapeutic Approaches with Their Clinical Relevance","volume":"99","author":"Gadhave","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","article-title":"Parkinson Disease","volume":"3","author":"Poewe","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","article-title":"Mutation in the \u03b1-Synuclein Gene Identified in Families with Parkinson\u2019s Disease","volume":"276","author":"Polymeropoulos","year":"1997","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1038\/s41436-019-0473-6","article-title":"De Novo and Biallelic DEAF1 Variants Cause a Phenotypic Spectrum","volume":"21","author":"Jensik","year":"2019","journal-title":"Genet. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"7071","DOI":"10.1038\/cddiscovery.2017.71","article-title":"Zinc-Finger Proteins in Health and Disease","volume":"3","author":"Cassandri","year":"2017","journal-title":"Cell Death Discov."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1093\/nar\/gkg161","article-title":"Structural Classification of Zinc Fingers: Survey and Summary","volume":"31","author":"Krishna","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"101148","DOI":"10.1016\/j.mam.2022.101148","article-title":"RNA Interference (RNAi)-Based Therapeutics for Treatment of Rare Neurologic Diseases","volume":"91","author":"Germain","year":"2023","journal-title":"Mol. Aspects Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1515\/nipt-2024-0013","article-title":"Oligonucleotide Therapeutics for Neurodegenerative Diseases","volume":"4","author":"Li","year":"2025","journal-title":"NeuroImmune Pharmacol. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/d41587-019-00014-7","article-title":"Billion-Dollar Deal Propels RNAi to CNS Frontier","volume":"37","author":"Sheridan","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"115073","DOI":"10.1016\/j.addr.2023.115073","article-title":"RNAi Therapies: Expanding Applications for Extrahepatic Diseases and Overcoming Delivery Challenges","volume":"201","author":"Kim","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/nrd2742","article-title":"Knocking down Barriers: Advances in SiRNA Delivery","volume":"8","author":"Whitehead","year":"2009","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/nrg3978","article-title":"Knocking down Disease: A Progress Report on SiRNA Therapeutics","volume":"16","author":"Wittrup","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1038\/nbt1339","article-title":"Mechanisms and Optimization of in Vivo Delivery of Lipophilic SiRNAs","volume":"25","author":"Wolfrum","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.jconrel.2010.02.011","article-title":"Lipophilic SiRNAs Mediate Efficient Gene Silencing in Oligodendrocytes with Direct CNS Delivery","volume":"144","author":"Chen","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nature03121","article-title":"Therapeutic Silencing of an Endogenous Gene by Systemic Administration of Modified SiRNAs","volume":"432","author":"Soutschek","year":"2004","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e266","DOI":"10.1038\/mtna.2015.38","article-title":"Hydrophobically Modified SiRNAs Silence Huntingtin MRNA in Primary Neurons and Mouse Brain","volume":"4","author":"Alterman","year":"2015","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jconrel.2019.06.022","article-title":"Chemical Modulation of SiRNA Lipophilicity for Efficient Delivery","volume":"307","author":"Tai","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41392-020-0207-x","article-title":"Therapeutic siRNA: State of the art","volume":"5","author":"Hu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1093\/nar\/23.11.2019","article-title":"Characterization of Fully 2\u2019-Modified Oligoribonucleotide Hetero-and Homoduplex Hybridization Andnuclease Sensitivity","volume":"23","author":"Cummins","year":"1995","journal-title":"Nucleic Acids Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1261\/rna.5239604","article-title":"In Vivo Activity of Nuclease-Resistant SiRNAs","volume":"10","author":"Layzer","year":"2004","journal-title":"RNA"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1093\/nar\/gkn1088","article-title":"Synthesis and Characterization of 2\u2032-Modified-4\u2032-ThioRNA: A Comprehensive Comparison of Nuclease Stability","volume":"37","author":"Takahashi","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1021\/jm049167j","article-title":"Fully 2\u2032-Modified Oligonucleotide Duplexes with Improved in Vitro Potency and Stability Compared to Unmodified Small Interfering RNA","volume":"48","author":"Allerson","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1016\/j.bmcl.2016.04.063","article-title":"Synergistic Effect of Phosphorothioate, 5\u2032-Vinylphosphonate and GalNAc Modifications for Enhancing Activity of Synthetic SiRNA","volume":"26","author":"Prakash","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.ymthe.2017.12.021","article-title":"Advanced SiRNA Designs Further Improve In Vivo Performance of GalNAc-SiRNA Conjugates","volume":"26","author":"Foster","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/s41467-018-02989-4","article-title":"Selection of GalNAc-Conjugated SiRNAs with Limited off-Target-Driven Rat Hepatotoxicity","volume":"9","author":"Janas","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"8537","DOI":"10.1021\/jacs.7b02694","article-title":"Chirality Dependent Potency Enhancement and Structural Impact of Glycol Nucleic Acid Modification on SiRNA","volume":"139","author":"Schlegel","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"7581","DOI":"10.1093\/nar\/gkx507","article-title":"5\u2019-Vinylphosphonate Improves Tissue Accumulation and Efficacy of Conjugated SiRNAs in Vivo","volume":"45","author":"Haraszti","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/cbic.201600130","article-title":"5\u2032-(E)-Vinylphosphonate: A Stable Phosphate Mimic Can Improve the RNAi Activity of SiRNA-GalNAc Conjugates","volume":"17","author":"Parmar","year":"2016","journal-title":"ChemBioChem"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41577-024-01104-7","article-title":"Neuroinflammation in Alzheimer Disease","volume":"25","author":"Heneka","year":"2025","journal-title":"Nat. Rev. Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/s41582-020-00435-y","article-title":"Neuroinflammation and Microglial Activation in Alzheimer Disease: Where Do We Go from Here?","volume":"17","author":"Leng","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"9215","DOI":"10.1002\/anie.202000451","article-title":"Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic","volume":"60","author":"Trist","year":"2021","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"458427","DOI":"10.1155\/2011\/458427","article-title":"SOD1 Transcriptional and Posttranscriptional Regulation and Its Potential Implications in ALS","volume":"2011","author":"Milani","year":"2011","journal-title":"Neurol. Res. Int."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1177\/1073858414561795","article-title":"SOD1 Function and Its Implications for Amyotrophic Lateral Sclerosis Pathology: New and Renascent Themes","volume":"21","author":"Saccon","year":"2015","journal-title":"Neuroscientist"},{"key":"ref_109","unstructured":"Alnylan Pharmaceuticals, Inc. (2025, July 05). Alnylam Reports Additional Positive Interim Phase 1 Results for ALN-APP, in Development for Alzheimer\u2019s Disease and Cerebral Amyloid Angiopathy. Available online: https:\/\/investors.alnylam.com\/press-release?id=27761."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e082650","DOI":"10.1002\/alz.082650","article-title":"Interim Phase 1 Part A Results for ALN-APP, the First Investigational RNAi Therapeutic in Development for Alzheimer\u2019s Disease","volume":"19","author":"Cohen","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_111","unstructured":"Cohen, S., and Meglio, M. (2025, December 15). Overviewing Encouraging Early-Stage Data on Mivelsiran, RNA Therapeutic for Alzheimer Disease: Sharon Cohen, MD, FRCPC. NeurologyLive. Available online: https:\/\/www.neurologylive.com\/view\/overviewing-encouraging-early-stage-data-mivelsiran-rna-therapeutic-alzheimers-sharon-cohen."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e084521","DOI":"10.1002\/alz.084521","article-title":"Single Ascending Dose Results from an Ongoing Phase 1 Study of Mivelsiran (ALN-APP), the First Investigational RNA Interference Therapeutic Targeting Amyloid Precursor Protein for Alzheimer\u2019s Disease","volume":"20","author":"Cohen","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Valdez-Gaxiola, C.A., Rosales-Leycegui, F., Gaxiola-Rubio, A., Moreno-Ortiz, J.M., and Figuera, L.E. (2024). Early- and Late-Onset Alzheimer\u2019s Disease: Two Sides of the Same Coin?. Diseases, 12.","DOI":"10.3390\/diseases12060110"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s11910-020-01090-y","article-title":"Early-Onset Alzheimer\u2019s Disease: What Is Missing in Research?","volume":"21","author":"Ayodele","year":"2021","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1038\/s41380-022-01531-9","article-title":"Dissecting the Clinical Heterogeneity of Early-Onset Alzheimer\u2019s Disease","volume":"27","author":"Sirkis","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1212\/CON.0000000000000687","article-title":"Early-Onset Alzheimer Disease and Its Variants","volume":"25","author":"Mendez","year":"2019","journal-title":"Contin. Lifelong Learn. Neurol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"173\u2013176; discussion 177\u2013178","DOI":"10.1017\/S1041610297004870","article-title":"Clinical Dementia Rating: A Reliable and Valid Diagnostic and Staging Measure for Dementia of the Alzheimer Type","volume":"9","author":"Morris","year":"1997","journal-title":"Int. Psychogeriatr."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","article-title":"\u201cMini-Mental State\u201d. A Practical Method for Grading the Cognitive State of Patients for the Clinician","volume":"12","author":"Folstein","year":"1975","journal-title":"J. Psychiatr. Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1111\/j.1532-5415.1992.tb01992.x","article-title":"The Mini-Mental State Examination: A Comprehensive Review","volume":"40","author":"Tombaugh","year":"1992","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13024-017-0231-7","article-title":"Practical Considerations for Choosing a Mouse Model of Alzheimer\u2019s Disease","volume":"12","author":"Jankowsky","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Oblak, A.L., Lin, P.B., Kotredes, K.P., Pandey, R.S., Garceau, D., Williams, H.M., Uyar, A., O\u2019Rourke, R., O\u2019Rourke, S., and Ingraham, C. (2021). Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.713726"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00401-007-0312-8","article-title":"Alzheimer Disease Models and Human Neuropathology: Similarities and Differences","volume":"115","author":"Duyckaerts","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13024-024-00712-0","article-title":"Updates on Mouse Models of Alzheimer\u2019s Disease","volume":"19","author":"Zhong","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_124","first-page":"e00019","article-title":"Animal Models of Alzheimer\u2019s Disease and Frontotemporal Dementia","volume":"9","author":"Ittner","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/msj.20159","article-title":"Transgenic Mouse Models of Alzheimer\u2019s Disease","volume":"77","author":"Elder","year":"2010","journal-title":"Mt. Sinai J. Med."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1590\/S1807-59322011001300006","article-title":"Insights into Alzheimer Disease Pathogenesis from Studies in Transgenic Animal Models","volume":"66","author":"Schaeffer","year":"2011","journal-title":"Clinics"},{"key":"ref_127","first-page":"45","article-title":"Transgenic Mouse Models of Alzheimer\u2019s Disease: An Integrative Analysis","volume":"23","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.jalz.2016.01.012","article-title":"Molecular Genetics of Early-Onset Alzheimer\u2019s Disease Revisited","volume":"12","author":"Cacace","year":"2016","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_129","first-page":"43","article-title":"Molecular Genetics of Early- and Late-Onset Alzheimer\u2019s Disease","volume":"21","author":"Uddin","year":"2020","journal-title":"Curr. Gene Ther."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1097\/NEN.0000000000000094","article-title":"MNos2 Deletion and Human NOS2 Replacement in Alzheimer Disease Models","volume":"73","author":"Colton","year":"2014","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1523\/JNEUROSCI.5066-07.2008","article-title":"Progression of Amyloid Pathology to Alzheimer\u2019s Disease Pathology in an Amyloid Precursor Protein Transgenic Mouse Model by Removal of Nitric Oxide Synthase 2","volume":"28","author":"Wilcock","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_132","unstructured":"Taillie, D., Cha, D., Ferraro, G., Bittner, K., Sostelly, A., Mooney, T., and Brown, K. (2025, January 27\u201331). Small Interfering RNA Targeting Amyloid-Beta Precursor Protein Reduces Alzheimer\u2019s Disease Pathology in 5xFAD Mice and Abrogates Behavior Changes in Early Intervention Paradigm. Proceedings of the Alzheimer\u2019s Association International Conference (AAIC), Toronto, ON, Canada."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal \u03b2-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer\u2019s Disease Mutations: Potential Factors in Amyloid Plaque Formation","volume":"26","author":"Oakley","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1750-1326-8-2","article-title":"Neuron Loss in the 5XFAD Mouse Model of Alzheimer\u2019s Disease Correlates with Intraneuronal A\u03b242 Accumulation and Caspase-3 Activation","volume":"8","author":"Eimer","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"P\u00e1dua, M.S., Guil-Guerrero, J.L., and Lopes, P.A. (2024). Behaviour Hallmarks in Alzheimer\u2019s Disease 5xFAD Mouse Model. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126766"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41597-021-01054-y","article-title":"Systematic Phenotyping and Characterization of the 5xFAD Mouse Model of Alzheimer\u2019s Disease","volume":"8","author":"Forner","year":"2021","journal-title":"Sci. Data"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.neuron.2024.12.025","article-title":"Parental Origin of Transgene Modulates Amyloid-\u03b2 Plaque Burden in the 5xFAD Mouse Model of Alzheimer\u2019s Disease","volume":"113","author":"Sasmita","year":"2025","journal-title":"Neuron"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/0165-0270(85)90031-7","article-title":"Validation of Open:Closed Arm Entries in an Elevated plus-Maze as a Measure of Anxiety in the Rat","volume":"14","author":"Pellow","year":"1985","journal-title":"J. Neurosci. Methods"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nprot.2007.44","article-title":"The Use of the Elevated plus Maze as an Assay of Anxiety-Related Behavior in Rodents","volume":"2","author":"Walf","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"196.e29","DOI":"10.1016\/j.neurobiolaging.2010.05.027","article-title":"Motor Deficits, Neuron Loss, and Reduced Anxiety Coinciding with Axonal Degeneration and Intraneuronal A\u03b2 Aggregation in the 5XFAD Mouse Model of Alzheimer\u2019s Disease","volume":"33","author":"Jawhar","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.physbeh.2014.05.041","article-title":"Behavioral and EEG Changes in Male 5xFAD Mice","volume":"135","author":"Schneider","year":"2014","journal-title":"Physiol. Behav."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s13023-015-0326-6","article-title":"Efficacy and Safety of Patisiran for Familial Amyloidotic Polyneuropathy: A Phase II Multi-Dose Study","volume":"10","author":"Suhr","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_143","first-page":"S129","article-title":"Phase 1 Study of ALN-TTRsc02, a Subcutaneously Administered Investigational RNAi Therapeutic for the Treatment of Transthyretin-Mediated Amyloidosis","volume":"175","author":"Adams","year":"2019","journal-title":"Rev. Neurol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1056\/NEJMoa1807838","article-title":"Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria","volume":"380","author":"Sardh","year":"2019","journal-title":"N. Engl. J. Med."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/1\/26\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T11:06:16Z","timestamp":1766487976000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/1\/26"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,22]]},"references-count":144,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ph19010026"],"URL":"https:\/\/doi.org\/10.3390\/ph19010026","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,22]]}}}