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. (Figure presented.)
Original language | English |
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Pages (from-to) | 520-537 |
Number of pages | 18 |
Journal | Journal of Neurochemistry |
Volume | 167 |
Issue number | 4 |
Early online date | 11 Oct 2023 |
DOIs | |
Publication status | Published - Nov 2023 |
Keywords
- Alzheimer's disease
- amyloid
- GSK3β
- leptin
- synapse
- tau