Evaluating the role of adiponectin on hippocampal synaptic function and on predicting dementia in patients with type 2 diabetes

Adiponectin is the most abundant adipokine secreted by adipose tissue, with insulin sensitising, anti-inflammatory and anti-atherogenic properties. Adiponectin exerts its effects through its receptors AdipoR1/2. Upon AdipoR activation, signalling pathways such as AMPK and PPARα are activated, transducing its effects at cellular level. AdipoRon is an adiponectin mimetic molecule intensely used in adiponectin research. Previous studies have focused in deciphering the role of adiponectin in skeletal muscle, liver and adipose tissue, however little is known about its role in the brain, and especially in the hippocampus. The hippocampus is a brain structure vital for learning and memory due to its synaptic plasticity and is one of the brain regions affected early in Alzheimer's disease (AD), the most common form of dementia. Adiponectin research has recently sparked interest due to reports of potential neuroprotective effects of adiponectin against the pathogenic mechanisms underlying AD. Moreover, epidemiological studies reported conflicting results regarding the association between adiponectin levels and dementia. To shed light on the adiponectin’s effects in the hippocampus, primary hippocampal neurons were treated with AdipoRon. AdipoRon increased the trafficking of GluA1-containing AMPARs (a cellular correlate of excitatory synaptic strength) in a time-dependent and concentration-dependent manner. Moreover, AdipoRon increased post-synaptic density of GluA1-containing AMPARs. This effect was mediated by AdipoRs, and it was dependent on the activation of GluN2A-containing NMDARs. Signalling pathways transducing the effects of AdipoRon on AMPAR trafficking involved a PI3K-dependent pathway and an AMPK-dependent process. PI3K activation led to GSK-3β inhibition, which mirrored and occluded the effects of AdipoRon on GluA1-containing AMPAR trafficking. AMPK activation caused an increase in phosphorylation of AMPK and ACC, a downstream target of phosphorylated AMPK. Subsequently, phosphorylated AMPK increased its synaptic localisation. Having deciphered the molecular mechanism transducing the effects of adiponectin in hippocampal neurons, its effects were next studied in an AD cellular model characterised by tau mis-localisation to dendrites and synaptic impairments. AdipoRon was able to rescue the increase in dendritic tau and the internalisation of GluA1-containing AMPARs, therefore suggesting that adiponectin has neuroprotective effects in this AD cellular model. To study the functional effects of adiponectin at hippocampal synapses, AdipoRon effects were investigated at excitatory SC-CA1 synapses. The effects of AdipoRon were dependent on concentration and duration of application. Application of AdipoRon 1µM for 20 min mimicked the effects of AdipoRon at cellular level, by increasing synaptic transmission. This increase was dependent on the activation of GluN2A-containing NMDARs and was mediated by AMPK activation. Further research is needed to further detangle the signalling pathways mediating the effects of adiponectin at excitatory SC-CA1 synapses in the hippocampus. To assess whether adiponectin is involved in modifying the risk of dementia or its subtypes AD or VD, the association between adiponectin plasma levels and the outcome of dementia, AD or VD was assessed in a prospective study enrolling 8,500 individuals. Plasma adiponectin levels almost reached significance in reducing the risk of AD and in increasing the risk of VD. More research is needed in order to confirm these observations, especially by assessing the association between CSF adiponectin levels and the outcome of dementia, AD or VD. In conclusion, adiponectin strengthens hippocampal excitatory synapses by increasing the trafficking of GluA1-containing AMPARs and consequently elevating the synaptic transmission. Moreover, adiponectin displays neuroprotective effects in an AD cellular model, raising the possibility of therapeutic approaches focused on adiponectin and AdipoR agonists. Furthermore, adiponectin levels might be associated with protective effects against AD, but further research is needed to assess whether CSF adiponectin reduced the risk of AD.