{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:50:09Z","timestamp":1782190209920,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Accumulation of aggregated amyloid beta (A\u03b2) species is a defining pathological hallmark of Alzheimer\u2019s disease and is associated with extensive neuronal structural abnormalities. Mild cognitive impairment (MCI), a transitional stage between normal aging and the onset of dementia, is thought to represent an early phase of this pathological continuum. Studies at the cellular level suggest that the conditions impair the maintenance of established neuronal processes\/networks and restrict their capacity for elongation or re-elongation. They may also attenuate the activation and process extension of quiescent neural progenitor or stem-like cells. These early cellular changes precede overt neurodegeneration in neural tissue and are likely to contribute to cognitive decline. They highlight the importance of in vitro models for identifying molecular targets involved in recovery from disease. In this study, we investigated the effects of aggregated A\u03b2 (25\u201335) on neuronal process elongation and associated intracellular events in the N1E-115 cell line, a widely used model of neuronal differentiation. Addition of aggregated A\u03b2 to cultured N1E-115 cells attenuated process elongation in a concentration-dependent manner. This morphological impairment was accompanied by decreased expression of neuronal differentiation markers. In contrast, at the half-maximal inhibitory concentration for process elongation, long-term cultured cells did not exhibit apparent process retraction or degenerative morphology. This mild but progressive impairment, without extensive cell death, is consistent with the cellular features of early-stage conditions rather than advanced Alzheimer\u2019s pathologies. Similar results were observed in primary cortical neurons. A\u03b2 also decreased the level of GTP-bound Ras and phosphorylation of the downstream mitogen-activated protein kinase\/extracellular signal-regulated kinase (MAPK\/ERK). Furthermore, treatment with hesperetin, a bioactive flavonoid compound, recovered the A\u03b2-induced inhibition of neuronal process elongation. Hesperetin also restored Ras and MAPK\/ERK states, suggesting that its effects are associated, at least in part, with modulation of signaling through Ras and MAPK\/ERK. Our findings suggest that hesperetin may serve as a useful molecular probe for modulating early cellular responses associated with Alzheimer\u2019s disease-related pathology. This in vitro model might serve as a useful platform for investigating the molecular target candidates involved in recovery from nervous system disorders.<\/jats:p>","DOI":"10.3390\/ijms27125481","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T15:11:22Z","timestamp":1781709082000},"page":"5481","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hesperetin Rescues Amyloid Beta-Induced Defects in Neurite Outgrowth Under In Vitro Mild Cognitive Impairment-like Cellular Conditions"],"prefix":"10.3390","volume":"27","author":[{"given":"Asahi","family":"Honjo","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2632-8488","authenticated-orcid":false,"given":"Hideji","family":"Yako","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuki","family":"Kasai","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikako","family":"Chiba","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayano","family":"Satsuka","sequence":"additional","affiliation":[{"name":"Strategic Planning Department, Oji Holdings Corporation, Koto, Tokyo 135-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohisa","family":"Kato","sequence":"additional","affiliation":[{"name":"Strategic Planning Department, Oji Holdings Corporation, Koto, Tokyo 135-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moeri","family":"Yagi","sequence":"additional","affiliation":[{"name":"Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 200-1192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0495-3023","authenticated-orcid":false,"given":"Akinori","family":"Nishi","sequence":"additional","affiliation":[{"name":"Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 200-1192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9298-5799","authenticated-orcid":false,"given":"Yuki","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan"},{"name":"Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3618-998X","authenticated-orcid":false,"given":"Junji","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan"},{"name":"Department of Biological Science, Tokyo College of Biotechnology, Oota, Tokyo 144-0032, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0140-6736(15)01124-1","article-title":"Alzheimer\u2019s disease","volume":"388","author":"Scheltens","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Liu, A.M. 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