This paper introduces an age-preserving neuronal iSpheroid platform that models human aging and Alzheimer's disease, revealing disease-associated metabolic changes and potential therapeutic targets.

bioRxiv · Oct 1, 2026 · PreprintNeuroscience

Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer's disease neurons

Larissa Traxler, Oliver Borgogno, Kylie Champion, Joseph R. Herdy, Monika Dzieciątkowska, Julie A. Reisz, Ayk Petrosyan, Cat Siler, Colin C. Anderson, Elisa Gorostieta-Salas, Raffaella Lucciola, Douglas Galasko, Fred H. Gage, Angelo D' Alessandro, Jérôme Mertens

This study shows that nuclear acetyl-CoA accumulation in Alzheimer's disease neurons causes RBP hyperacetylation and splicing shifts, which can be reversed by inhibiting ACLY.

bioRxiv · Oct 1, 2026 · PreprintNeuroscience

Cytoplasmic DNA Sensing Links LINE-1 Expression to Neuronal Senescence in Alzheimer's Disease

Joseph R. Herdy, Emma E Taylor, Lukas Karbacher, Oliver Borgogno, Larissa Traxler, Jessica Lagerwall, Vincent A. Huynh, Zornitsa V Lefterova, Austin Kang, Carlota Tosat‐Bitrián, Maxfield M. G. Kelsey, John M. Sedivy, Subhash C. Sinha, Li Gan, C. Frank Bennett, , Fred H. Gage

This study identifies LINE-1 retrotransposons as drivers of neuronal senescence in Alzheimer's disease through cytoplasmic DNA sensing and the cGAS-STING pathway.

bioRxiv · Jul 28, 2026 · PreprintNeuroscience

A Toxic Tau-PFKFB3 Circuit Reduces F2,6BP Levels and Drives Neurodegeneration

Santi M Mandal, Anirban Chakraborty, Shandy Shahabi, Mikita Mankevich, Adrián Povo‐Retana, Tapan Biswas, Sergio Sánchez‐García, Sravan Gopalkrishnashetty Sreenivasmurthy, Lucia Zhou Yang, Joseph R. Herdy, Jérôme Mertens, Fred H. Gage, Johannes C. M. Schlachetzki, Balaji Krishnan, Lisardo Boscá, , Gourisankar Ghosh

This paper identifies the PFKFB3-F2,6BP metabolic axis as a key driver of Alzheimer's disease by linking metabolic dysregulation to genomic stability and Tau proteostasis, showing that F2,6BP supplementation rescues AD phenotypes across multiple models.

bioRxiv · May 31, 2026 · PreprintNeuroscience

Autophagy flux during human aging is sex- and cell type-specific, and is associated with physical fitness

Tatiana M. Moreno, Stephanie Heimler, Ryan J. Moran, Hava‐Shoshana Barkai, Lina Scandalis, Larissa Traxler, Ashley Neil, Stephen Dozier, Jaclyn Bergstrom, Sanjeev S. Ranade, Anne G. Bang, Jérôme Mertens, David Wing, Anthony J. A. Molina, Caroline Kumsta

This study examines autophagy flux changes with age in human cell types, finding sex- and cell-type-specific patterns and a link to physical fitness.

bioRxiv · May 21, 2026 · PreprintCell Biology

Impaired lipoprotein secretion by APOE4 leads to lysosomal and mitochondrial dysfunction in human microglia

Jasmin S. Revanna, Karl A. Wessendorf-Rodriguez, Qiang Xiao, Thaís S. Sabedot, Michael S. Cuoco, Snigdha Sarkar, Lucia Zhou-Yang, Christina K. Lim, Victoria N. Prozapas, Rowan S. Wooldridge, Jean Paul Chadarevian, Joshua M. Pratt, Sheila C. Steiner, Ava Katz, Jérôme Mertens, , Fred H. Gage

This study shows that APOE4 impairs lipoprotein secretion in microglia, leading to lysosomal and mitochondrial dysfunction and a proinflammatory phenotype.

bioRxiv · May 13, 2026 · PreprintNeuroscience

RUNX1 and YY1 modulate neuronal fate and energy metabolism in Alzheimer's disease

Raffaella Lucciola, Joseph R. Herdy, Yatavee Vajaphattana, Lukas Karbacher, Thaís S. Sabedot, Michael S. Cuoco, Larissa Traxler, Austin Kang, Mack B. Reynolds, Jeffrey R. Jones, Simon T. Schafer, Jérôme Mertens, Fred H. Gage

This study identifies RUNX1 and YY1 as master transcription factors modulating neuronal fate and energy metabolism in Alzheimer's disease using patient-derived induced neurons and post-mortem brain data.

bioRxiv · Apr 14, 2026 · PreprintNeuroscience