Transcriptomic alterations in APP/PS1 mice astrocytes lead to early postnatal axon initial segment structural changes

Area of Science:

• Neuroscience
• Cell Biology
• Neurodegenerative Diseases

Background:

• Alzheimer's disease (AD) involves neuronal dysfunction and degeneration.
• The axon initial segment (AIS) is critical for neuronal function, and its alterations are observed in AD.
• The glial contribution to AIS deregulation in AD remains unclear.

Purpose of the Study:

• To investigate early postnatal AIS mechanisms in wild-type and APP/PS1 mice.
• To explore the role of astrocytes in AIS modulation in the context of AD.
• To identify potential therapeutic targets for preventing AIS dysfunction in AD.

Main Methods:

• Comparative analysis of AIS in wild-type and APP/PS1 mice from postnatal day 21 (P21).
• Neuron-astrocyte co-culture experiments to assess astrocyte influence on AIS.
• Molecular analysis of retinoic acid synthesis enzymes, ADNP, and P2X7 receptor pathways.
• In vivo treatment with P2X7 inhibitors in APP/PS1 mice.

Main Results:

• APP/PS1 mice exhibited AIS integrity loss, reduced ankyrinG expression, and AIS shortening from P21.
• APP/PS1 astrocytes induced AIS integrity loss in wild-type neurons.
• Reduced expression of retinoic acid synthesis enzymes (Rdh1, Aldh1b1) and ADNP in APP/PS1 astrocytes contributed to AIS changes.
• AIS integrity in wild-type neurons was restored by inhibiting retinoic acid degradation, adding NAP peptide, or inhibiting P2X7 receptors.
• Long-term P2X7 inhibitor treatment ameliorated AIS disruption in APP/PS1 mice.

Conclusions:

• Astrocytes play a significant role in modulating AIS integrity early in postnatal development.
• Alterations in astrocytes, including reduced ADNP and altered retinoic acid signaling, can lead to AIS dysfunction.
• Targeting glial cell pathways, such as P2X7 receptors, may offer novel therapeutic strategies for early AD intervention.