UC San Diego

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease regarded as a multifactorial disorder, a condition caused by multiple factors. With the majority of AD patients aged 65 and older, age is one of the strongest risk factors for AD, but its causes are not fully understood. Previous transcriptomic profiling of AD neurons identified a list of differentially expressed genes unique to AD; YY1, RUNX1, NFIB, and PPARγ emerged as some of the most upregulated transcription factors (TFs) reportedly associated with biological dysfunctions phenotypic of AD in various cell types. However, their function in aged neurons remains unknown. To investigate the possible contributions of YY1, RUNX1, NFIB, and PPARγ to AD pathology, we questioned their ability to reproduce AD-related phenotypes in aged neurons by characterizing transcriptomic changes caused by individual overexpression of each TF. We utilized induced neurons (iNs) produced from the reprogramming of old, healthy, donor-derived fibroblasts directly into neurons as a human-relevant means of capturing the age. All four TFs retain aspects of their previously described functions in old iNs with YY1 regulating the metabolic program, RUNX1 restricting neuronal identity, PPARγ regulating lipid metabolism and inflammation, and NFIB promoting the expression of developmental genes, possibly facilitating oncogenic transformations and contributing to the vulnerable hypo-mature state seen in AD neurons. Further investigation confirmed that YY1 and RUNX1’s transcriptomic effects are functionally translatable, identifying them as potential targets for medical intervention.