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Along with this, various midbrain-target areas are characterized by neuroinflammation since the MCI stage. The concomitance of neuroinflammation, \u0391\u03b2 and tau appears to be a strong predictor for conversion from MCI to dementia.<\/jats:p>\n            <jats:p>Yet, how midbrain degeneration could cause disease progression, and what mechanisms are involved in triggering neuroinflammation in midbrain-target areas such as the hippocampus remain unexplored.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Using adult C57BL\/6N mice we generated a new mouse model carrying lesions in three midbrain nuclei, the dopaminergic Ventral Tegmental Area (VTA) and Substantia Nigra <jats:italic>pars compacta<\/jats:italic> (SNpc) and the serotonergic Interpeduncular Nucleus (IPN), to evaluate the consequences of dopamine and serotonin deprivation in midbrain-target areas. We characterized this model by performing stereological cell counts, analysis of monoaminergic fibers, monoamine levels, electrophysiology and behavioral tests. We then assessed hippocampal neuroinflammation by analyzing glia cell count, changes in morphology, NLRP3 inflammasome activation and cytokine levels, and microglia transcriptional profiling. In a separate set of experiments, we induced experimental midbrain lesion in Tg2576 transgenic mice overexpressing the Swedish mutant amyloid precursor protein, to evaluate the effect of monoamine deprivation on the hippocampus in concomitance with amyloid-\u03b2 (A\u03b2) accumulation.\u00a0The lesion performed in Tg2576 mice, as opposed to that in C57BL\/6N mice, provides valuable insights into how neuroinflammation is influenced by A\u03b2 accumulation versus the exclusive impact of impaired monoaminergic signaling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The concomitant depletion of dopaminergic and serotonergic inputs within the hippocampus of C57BL\/6N mice provokes a pronounced activation of microglia <jats:italic>via<\/jats:italic> the NLRP3-inflammasome pathway, accompanied by increased IL-1\u03b2 expression. Pharmacological intervention with either dopaminergic (L-DOPA or A68930) or serotonergic (fluoxetine) agents abrogates this neuroinflammatory response. In the Tg2576 transgenic mouse model of amyloid pathology, which exhibits progressive A\u03b2 deposition, superimposed midbrain degeneration markedly amplifies AD-like neuropathology. This includes exacerbation of microglial reactivity, robust astrocyte response, precocious A\u03b2 plaque burden, and induction of pathological tau hyperphosphorylation. Notably, administration of L-DOPA or fluoxetine significantly attenuates both the astrocyte reactivity and tau hyperphosphorylation in the lesioned Tg2576 cohort.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>These results highlight the pivotal role of midbrain damage for the amplification of neuroinflammatory cascades and AD pathology. Moreover, they offer mechanistic insight into the faster progression to dementia in patients with midbrain deficits. By translating these findings into clinical practice, we can advance towards a precision medicine approach in disease management.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13024-025-00893-2","type":"journal-article","created":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T23:02:19Z","timestamp":1760310139000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer\u2019s Disease"],"prefix":"10.1186","volume":"20","author":[{"given":"Livia","family":"La Barbera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paraskevi","family":"Krashia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilda","family":"Loffredo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Cauzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"De Paolis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Montanari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana","family":"Saba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Spoleti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Ficch\u00ec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Zaccone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"De Bardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Palazzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramona","family":"Marino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele Claudio","family":"Latagliata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Puglisi-Allegra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Borsellino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Lo Iacono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Viscomi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Nobili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"D\u2019Amelio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"issue":"8","key":"893_CR1","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1056\/NEJMoa2310168","volume":"390","author":"J Jia","year":"2024","unstructured":"Jia J, Ning Y, Chen M, Wang S, Yang H, Li F, et al. 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