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@ARTICLE{Cinar:281436,
      author       = {Cinar, Elif and Yalcin-Cakmakli, Gül and Akyel, Hilal and
                      Ulusoy, Ayse and Tel, Banu Cahide and Elibol, Bülent},
      title        = {{A}utophagy activation ameliorates cognitive deficits and
                      alpha-synuclein pathology in an adeno-associated viral
                      vector mediated rat model of {L}ewy body disorders.},
      journal      = {Pharmacology, biochemistry and behavior},
      volume       = {257},
      issn         = {0091-3057},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DZNE-2025-01121},
      pages        = {174096},
      year         = {2025},
      abstract     = {Lewy body disorders (LBD), including Parkinson's disease
                      (PD), Parkinson's disease with dementia (PDD), and dementia
                      with Lewy bodies (DLB), are characterized by the aggregation
                      of alpha-synuclein (a-syn). Despite shared pathological
                      features, these disorders have distinct clinical
                      characteristics, in terms of both motor and cognitive
                      symptoms. We created a unique rat model of dual-site
                      injection of adeno-associated viral vectors carrying human
                      a-syn (AAV5-h-a-syn) simultaneously and bilaterally into the
                      substantia nigra and dentate gyrus, to recapitulate both
                      nigrostriatal and hippocampal-based a-syn pathology
                      associated with PDD and DLB. Inspired by the distinct
                      pathological features of the model, namely the CA2-dominated
                      accumulation of phosphorylated a-syn, in the current study
                      we aimed to evaluate comparatively the consequences of
                      autophagic induction on a-syn pathology in these targeted
                      areas. This was achieved by the chronic administration of
                      rapamycin, for 8 weeks starting 10 weeks post-AAV
                      injections. Behavioral assessments were conducted by
                      evaluation of locomotor activity, anxiety-related behavior,
                      object and spatial learning and memory. Histopathological
                      examinations involved in-depth analysis of a-syn pathology,
                      neuronal and synaptic integrity and autophagic markers.
                      Results demonstrated that rapamycin significantly
                      ameliorated cognitive deficits and reduced phosphorylated
                      a-syn accumulation, significantly in CA2 throughout all its
                      sublayers and partially in CA3 sublayers. Despite no
                      alteration in NeuN and TH levels, synaptophysin expressions
                      were decreased in both the hippocampus and striatum in a-syn
                      overexpressing animals, which were partially restored by
                      rapamycin treatment. Intriguingly, autophagic activation, as
                      indicated by the increased expression of beclin-1, LC3-I/II,
                      p62, and Atg proteins, was predominantly observed in the
                      hippocampus but not in the striatum, suggesting
                      region-specific differential response to autophagic
                      induction in terms of a-syn pathology. This dual-site
                      injection model provides a valuable tool for studying
                      a-syn-related dementia and evaluating potential restorative
                      therapies. Our findings underscore the importance of
                      autophagy-targeting early interventions to alleviate
                      cognitive deficits by reducing hippocampal a-syn burden in
                      LBD.},
      keywords     = {Animals / alpha-Synuclein: metabolism / alpha-Synuclein:
                      genetics / Autophagy: drug effects / Autophagy: physiology /
                      Rats / Dependovirus: genetics / Lewy Body Disease: pathology
                      / Lewy Body Disease: metabolism / Lewy Body Disease:
                      psychology / Lewy Body Disease: therapy / Male / Disease
                      Models, Animal / Genetic Vectors / Cognitive Dysfunction:
                      therapy / Sirolimus: pharmacology / Humans / Rats,
                      Sprague-Dawley / Alpha-synucleinopathies (Other) / CA2
                      (Other) / Dementia (Other) / Hippocampus (Other) /
                      Parkinson's disease (Other) / Rapamycin (Other) / Stratum
                      pyramidale (Other) / Synaptic integrity (Other)},
      cin          = {AG Ulusoy},
      ddc          = {540},
      cid          = {I:(DE-2719)1013044},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40939811},
      doi          = {10.1016/j.pbb.2025.174096},
      url          = {https://pub.dzne.de/record/281436},
}