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@INPROCEEDINGS{Song:283110,
      author       = {Song, Xiaoxuan and de Vecchi, Teodoro and Widmann, Jeannine
                      and Fierli, Federico and Ruf, Viktoria and Tang, Qilin and
                      Arzberger, Thomas and Roeber, Sigrun and Köglsperger,
                      Thomas and Windl, Otto and Haass, Christian and Winkelmann,
                      Juliane and Herms, Jochen and Strübing, Felix},
      title        = {{A}lpha‐{S}ynuclein co‐pathology drives tau
                      accumulation in {A}lzheimer's disease patients and
                      i{PSC}s‐derived models},
      journal      = {Alzheimer's and dementia},
      volume       = {21},
      number       = {S1},
      issn         = {1552-5260},
      reportid     = {DZNE-2026-00006},
      pages        = {e106193},
      year         = {2025},
      abstract     = {Background:The molecular basis for accelerated cognitive
                      decline seen in Alzheimer's Disease (AD) cases presenting
                      with cortical alpha-Synuclein co-pathology is not well
                      understood. Mouse experiments have shown adverse
                      interactions between tau (encoded by MAPT) and
                      alpha-Synuclein (encoded by SNCA), but how this finding
                      translates to humans from a genome-centered point of view
                      remains unknown.Method:Whole genome sequencing was performed
                      on 137 neuropathologically defined AD cases, 36 of which
                      presented with neocortical alpha-Synuclein co-pathology
                      (Braak stage 6). Polygenic risk scores were calculated.
                      Single-nucleus RNA sequencing and Western Blot data were
                      collected from post-mortem tissue. Transcriptomic and
                      proteomic results were validated in the MSBB cohort (n
                      >300). Cellular, molecular and epigenetic consequences were
                      assessed in isogenic iPSCs-derived neurons carrying a
                      triplication of SNCA (AST) or a normal SNCA copy number
                      (CAS).Result:AD brains with alpha-Synuclein co-pathology had
                      significantly higher polygenic risk scores for Parkinson's
                      Disease, which could be partially explained by variants
                      associated with higher expression of SNCA. Single-nucleus
                      RNA sequencing and immunoblot analysis revealed a higher
                      expression of MAPT and phosphorylated tau in alpha-Synuclein
                      co-pathology cases. Protein and mRNA expression of MAPT and
                      SNCA were positively correlated in the MSBB cohort. The
                      employed iPSCs differentiation protocol accelerated neuronal
                      maturation due to transient inhibition of EZH2. Day50 AST
                      neurons exhibited significantly increased pathological tau
                      and alpha-Synuclein at both the RNA and protein levels
                      compared to CAS neurons. AST neurons also showed highly
                      activated GSK3β and decreased PSD95 (post-synaptic protein)
                      in the immunofluorescence and immunoblot analyses. ATAC
                      profiles identified dysregulated accessibility in the cAMP
                      signaling pathway, as well as pathways related to axon
                      guidance, postsynaptic density, and calcium signaling, among
                      others.Conclusion:We demonstrate that alpha-Synuclein
                      co-pathology in AD is characterized by higher phosphorylated
                      tau levels in patients and iPSC-derived neurons. Our results
                      provide insights into the complex molecular processes
                      through which alpha-Synuclein and tau synergistically drive
                      dementia-related pathology.},
      month         = {Jul},
      date          = {2025-07-27},
      organization  = {Alzheimer’s Association
                       International Conference, Toronto
                       (Canada), 27 Jul 2025 - 31 Jul 2025},
      cin          = {AG Herms / Clinical Research (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1110001 / I:(DE-2719)1111015},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)1 / PUB:(DE-HGF)16},
      doi          = {10.1002/alz70855_106193},
      url          = {https://pub.dzne.de/record/283110},
}