Leptin prevents aberrant targeting of tau to hippocampal synapses via PI 3 kinase driven inhibition of GSK3β

Abstract Amyloid‐β (Aβ) and hyper‐phosphorylated tau are key hallmarks of Alzheimer's disease (AD), with an accumulation of both proteins linked to hippocampal synaptic dysfunction. Recent evidence indicates that Aβ drives mis‐localisation of tau from axons to synapses, resulting in AMPA receptor (AMPAR) internalisation and impaired excitatory synaptic function. These tau‐driven synaptic impairments are thought to underlie the cognitive deficits in AD. Consequently, limiting the synapto‐toxic effects of tau may prevent AD‐related cognitive deficits. Increasing evidence links leptin dysfunction with higher AD risk, and numerous studies have identified neuroprotective properties of leptin in AD models of Aβ‐induced toxicity. However, it is unclear if leptin protects against tau‐related synaptic dysfunction. Here we show that Aβ 1‐42 significantly increases dendritic and synaptic levels of tau and p‐tau in hippocampal neurons, and these effects were blocked by leptin. In accordance with GSK‐3β being involved in tau phosphorylation, the protective effects of leptin involve PI 3‐kinase (PI3K) activation and inhibition of GSK‐3β. Aβ 1‐42 ‐driven synaptic targeting of tau was associated with the removal of GluA1‐containing AMPARs from synapses, which was also inhibited by leptin‐driven inhibition of GSK‐3β. Direct application of oligomeric tau to hippocampal neurons caused internalisation of GluA1‐containing AMPARs and this effect was blocked by prior application of leptin. Similarly, leptin prevented the ability of tau to block induction of activity‐dependent long‐term potentiation (LTP) at hippocampal SC‐CA1 synapses. These findings increase our understanding of the neuroprotective actions of leptin in the early pre‐clinical stages of AD and further validate the leptin system as a therapeutic target in AD. image