Gene dysregulation is one of the key mechanisms that link pathological abnormalities to cognitive impairment in Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. Our transcriptomic analysis of large-scale postmortem AD human prefrontal cortex (PFC) data revealed that complement genes, a key player in modulating tissue homeostasis and immune surveillance, were prominently upregulated.
Objective
The goal of this study is to reveal key transcriptional regulators that contribute to the elevation of complement genes in AD.
Methods
Transcriptomic and epigenomic analyses, molecular, biochemical and immunocytochemical assays, and in vivo gene manipulation, were used.
Results
Our epigenomic analysis identified ADNP (activity-dependent neuroprotective protein), a chromatin regulator strongly linked to intellectual disability, as one of the top-ranking transcription factors regulating complement genes. ADNP and its partner HP1γ (Heterochromatin protein 1) were found to be significantly diminished in postmortem AD human PFC. Reduced Adnp expression was also found in PFC of a familial AD mouse model, 5xFAD. Knockdown of Adnp in mice led to the significantly increased levels of complement genes, reminiscent to complement gene elevation in postmortem AD humans and 5xFAD mice. Furthermore, human induced pluripotent stem cell-derived neuronal cultures from AD patients exhibited astrocyte activation, ADNP/HP1γ reduction, and complement gene increase. Manipulation of ADNP levels led to bidirectional changes in complement gene expression.
Conclusions
These data suggest that the diminished ADNP in AD could lead to chromatin dysregulation because of disrupted transcriptional repression, which contributes to the elevation of complement genes. It provides a novel upstream epigenetic modifier for gene dysregulation in AD.
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