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 Aβ1‐42 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. Aβ1‐42‐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

Experimental laboratory models as tools for understanding modifiable dementia risk

“…Some obesity‐related brain changes may be caused by dysregulation of adipokines such as leptin, which are secreted by adipose tissue and can influence plasticity, neurogenesis and inflammatory cytokine production in dementia‐relevant brain regions such as the hippocampus 205 . Studies in AD models have suggested that leptin may have a therapeutic role in reducing Aβ and intracellular tau phosphorylation, thereby preventing synaptic dysfunction 190,191,206–208 . Work in wild‐type animals suggests that the developmental timing of obesity may be important, since poor diet (high‐fat or high sugar) in adolescence, more than in adulthood, causes cognitive defects 209 .…”

“… 205 Studies in AD models have suggested that leptin may have a therapeutic role in reducing Aβ and intracellular tau phosphorylation, thereby preventing synaptic dysfunction. 190 , 191 , 206 , 207 , 208 Work in wild‐type animals suggests that the developmental timing of obesity may be important, since poor diet (high‐fat or high sugar) in adolescence, more than in adulthood, causes cognitive defects. 209 With a short 21‐day lifespan and high amenity to genetic manipulation, C. elegans models of aging and human Aβ overexpression hold future promise for investigating food intake and fat accumulation relevant to obesity (reviewed in Ref.…”