XBP1s as a Therapeutic Target to Preserve Retinal Function During Aging and Neurodegeneration

Medina, L. E.; Barria, J.; Chacon, M.; Orellana, M.; Ponce, D.; Neira, D.; Miqueles, F.; Duran-Aniotz, C.; Araya-Arriagada, J.; Cerda, B.; Hetz, C.; Rojas, C.; Palacios, A. G.

doi:10.1101/2025.07.03.662890

bioRxiv · 10.1101/2025.07.03.662890

XBP1s as a Therapeutic Target to Preserve Retinal Function During Aging and Neurodegeneration

Medina, L. E.·Barria, J.·Chacon, M.·Orellana, M.·Ponce, D.·Neira, D.·Miqueles, F.·Duran-Aniotz, C.·Araya-Arriagada, J.·Cerda, B.·Hetz, C.·Rojas, C.·Palacios, A. G.

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Abstract

Loss of physiological complexity, characterized by reduced adaptive multiscale coordination among system components, is increasingly recognized as a hallmark of aging and neurodegenerative disease. The retina, a window into the brain, offers a unique, accessible platform to monitor neurodegenerative disorders such as Alzheimers disease (AD). Here, we investigate the therapeutic potential of the unfolded protein response transcription factor XBP1s in preserving retinal function during aging and AD-related pathology in murine models. Using micro-electroretinography with multielectrode arrays, we recorded retinal responses to chirp and white noise stimuli in four mouse models: wild-type (WT), XBP1s-overexpressing (TgXBP1s), AD model (5xFAD), and their crossbreed (TgXBP1s/5xFAD) at approximately 3 and 7 months of age. We assessed retinal signals through entropy-based complexity measures and wavelet coherence between stimulus and response. While WT and 5xFAD mice exhibited age-related decline in retinal complexity, TgXBP1s and TgXBP1s/5xFAD mice maintained higher complexity levels and increased Wcoh in adulthood, indicating functional preservation. These results demonstrate that sus-tained XBP1s expression protects retinal electrophysiological integrity and highlight the retinas value as a scalable, noninvasive biomarker platform to evaluate therapeutic efficacy targeting neurodegenerative mechanisms.

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Medina, L. E., Barria, J., Chacon, M., Orellana, M., Ponce, D., Neira, D., Miqueles, F., Duran-Aniotz, C., Araya-Arriagada, J., Cerda, B., Hetz, C., Rojas, C., Palacios, A. G.. 2025-07-04. XBP1s as a Therapeutic Target to Preserve Retinal Function During Aging and Neurodegeneration. https://doi.org/10.1101/2025.07.03.662890

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