Diminished activity-dependent neuroprotective protein (ADNP) contributes to complement gene elevation in Alzheimer's...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Gene dysregulation links Alzheimer's disease (AD) pathology to cognitive impairment.
• Complement genes are upregulated in the prefrontal cortex (PFC) of AD patients.
• Complement genes modulate tissue homeostasis and immune surveillance.

Purpose of the Study:

• Identify key transcriptional regulators of complement gene elevation in AD.
• Investigate the role of ADNP (activity-dependent neuroprotective protein) in AD pathogenesis.
• Explore epigenetic mechanisms underlying gene dysregulation in Alzheimer's disease.

Main Methods:

• Transcriptomic and epigenomic analyses were performed on human postmortem PFC.
• Molecular, biochemical, and immunocytochemical assays were utilized.
• In vivo gene manipulation in mouse models and iPSC-derived neuronal cultures were conducted.

Main Results:

• ADNP, a chromatin regulator, was identified as a top transcription factor for complement genes in AD.
• ADNP and HP1γ (Heterochromatin protein 1) levels were diminished in postmortem AD PFC and 5xFAD mouse models.
• Reduced ADNP expression in mice led to increased complement gene levels, mimicking AD conditions.
• Patient-derived neuronal cultures showed astrocyte activation, reduced ADNP/HP1γ, and elevated complement genes.

Conclusions:

• Diminished ADNP in AD may cause chromatin dysregulation via disrupted transcriptional repression.
• This epigenetic mechanism contributes to the elevation of complement genes in Alzheimer's disease.
• ADNP represents a novel upstream epigenetic modifier for gene dysregulation in AD.