AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma.

Area of Science:

• Neuroscience
• Cell Biology
• Ophthalmology

Background:

• Neuronal function, including dendritic arborization and synaptic transmission, is energy-intensive.
• Bioenergetic decline is a hallmark of neurodegenerative diseases, but the underlying signaling pathways remain unclear.
• Glaucoma involves energy deficits, leading to retinal ganglion cell (RGC) dendritic pathology and synapse loss.

Purpose of the Study:

• To investigate the role of adenosine monophosphate-activated protein kinase (AMPK) in RGC dysfunction under pressure-induced stress.
• To elucidate the signaling mechanisms linking energy stress to RGC damage in glaucoma.

Main Methods:

• Activation of AMPK was assessed in RGCs from mouse models of ocular hypertension and human glaucoma patients.
• The impact of AMPK on RGC dendrite morphology and synaptic integrity was evaluated.
• The role of mammalian target of rapamycin complex 1 (mTORC1) in AMPK-mediated RGC dysfunction was examined.
• Functional recovery of RGCs following AMPK modulation was assessed through light-evoked responses, axonal transport, and survival assays.

Main Results:

• AMPK is significantly activated in RGCs under ocular hypertension and in primary open-angle glaucoma.
• Activated AMPK induces RGC dendrite retraction and synapse elimination by inhibiting mTORC1.
• Reducing AMPK activity restores mTORC1 function, rescuing dendritic structures and synaptic contacts.
• AMPK inhibition promotes recovery of visual function, improves axonal transport, and enhances RGC survival.

Conclusions:

• AMPK acts as a key mediator connecting bioenergetic decline with RGC dysfunction in pressure-induced ocular stress.
• Targeting energy homeostasis, specifically modulating AMPK activity, is a promising therapeutic strategy for glaucoma and other neurodegenerative conditions.