Jerome Mertens

Department for Neurosciences ofthe University of California San Diego, USA

Neurodegenerative   disorders   such   as   Alzheimer’s    Disease   (AD) overwhelmingly affects humans at old age, yet most existing research relies  on  transgenic  models  for  rare  genetic variants, which  don’t adequately capture the complexities of human genetics and aging. While iPSC neurons are promising, their reprogramming process erases age-related features, producing neurons that are more‘youthful’than those   affected   in   sporadic  AD.   In   contrast,   directly  converting

fibroblasts   into   induced   neurons   (iNs)   preserves   cellular   aging,

providing a valuable tool for modeling the authentic aging brain. In this seminar, I will present work where we compare age-equivalent iNs form healthy old donors and AD patients, as well as rejuvenated   neurons  from  AD   patients,.   Our   study   reveals   that   adult-like   iNs   capture disease-associated  signatures  that  mirror  findings  from  transcriptomic  and  pathological analyses. Intriguingly, we find that age-equivalent iNs demonstrate stress markers and metabolic changes, and share features with cellular programs seen in cancer biology, opening new avenues for understanding neuronal vulnerability in AD. A key message of our data is that maintaining biological age in patient-derived neuronal models is critical for uncovering disease mechanisms relevant to late-onset neurodegenerative conditions.