CNS neuroscience & therapeutics · 2025
Adiponectin Receptor Agonist Ameliorates Synaptic Dysfunction in 3xTg Alzheimer's Disease Mouse Model by Activation of AMPK.
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Bloemer Jenna, Pinky Priyanka D, Suppiramaniam Vishnu, Reed Miranda N
Аннотация
AIM: The hormone adiponectin impacts various facets of brain function, including neurogenesis, energy homeostasis, and synaptic processes. The use of adiponectin or adiponectin receptor agonists may protect against Alzheimer's disease (AD) and reduce AD pathology. Here, we investigated the ability of the adiponectin receptor agonist, AdipoRon, to restore synaptic function in an AD mouse model and the underlying mechanism.
METHODS: Acute hippocampal slices from 3xTg-AD mice and age-matched controls were used to evaluate the ability of AdipoRon to rescue synaptic deficits in an AD model. Slices were incubated in AdipoRon or other pharmacological agents, followed by electrophysiological field recordings to evaluate synaptic function and plasticity. Signaling pathway alterations were evaluated by Western blot, with a focus on AMP-activated protein kinase (AMPK) signaling.
RESULTS: Incubation of hippocampal slices with AdipoRon ameliorated long-term potentiation (LTP) and basal synaptic transmission deficits in 3xTg-AD mice. AdipoRon was unable to restore these parameters in the presence of the AMPK inhibitor, Compound C. AdipoRon altered presynaptic parameters by a mechanism that did not appear to be solely dependent on AMPK. AdipoRon slice incubation was associated with activation of AMPK, inhibition of GSK3β, and altered glutamatergic receptor subunit phosphorylation based on Western blot analysis.
CONCLUSION: Activation of adiponectin receptors restores synaptic function in an AD model in part through AMPK signaling. These results warrant further investigation into adiponectin receptor agonists as a novel approach for AD prevention or treatment.
METHODS: Acute hippocampal slices from 3xTg-AD mice and age-matched controls were used to evaluate the ability of AdipoRon to rescue synaptic deficits in an AD model. Slices were incubated in AdipoRon or other pharmacological agents, followed by electrophysiological field recordings to evaluate synaptic function and plasticity. Signaling pathway alterations were evaluated by Western blot, with a focus on AMP-activated protein kinase (AMPK) signaling.
RESULTS: Incubation of hippocampal slices with AdipoRon ameliorated long-term potentiation (LTP) and basal synaptic transmission deficits in 3xTg-AD mice. AdipoRon was unable to restore these parameters in the presence of the AMPK inhibitor, Compound C. AdipoRon altered presynaptic parameters by a mechanism that did not appear to be solely dependent on AMPK. AdipoRon slice incubation was associated with activation of AMPK, inhibition of GSK3β, and altered glutamatergic receptor subunit phosphorylation based on Western blot analysis.
CONCLUSION: Activation of adiponectin receptors restores synaptic function in an AD model in part through AMPK signaling. These results warrant further investigation into adiponectin receptor agonists as a novel approach for AD prevention or treatment.