High-fat diet robustly increases CA1 stratum radiatum synaptic density and may modify AppNL-F-enhanced plasticity in old mice
Obesity and high-fat diet (HFD) are linked to increased Alzheimer’s disease (AD) risk, but effects on aged hippocampal synapses remain unclear
TREM2R47H is an AD risk variant that alters microglial responses to amyloid pathology and synaptic remodelling
This study tested whether long-term HFD and/or Trem2R47H/R47H affect CA1 stratum radiatum (SR) synaptic plasticity and excitatory synapse density in aged AppNL-F/NL-F knock-in mice.
AppNL-F enhances SR short- and long-term potentiation without altering basal synaptic transmission in 22–26-month-old mice under control-diet. No effect of the Trem2R47H mutation
HFD reduces SR Short-term potentiation and trends toward lower long-term potentiation in AppNL-F in 22–26-month-old mice
HFD and Trem2R47H increase synaptic density in CA1 SR in 22–26-month-old mice
In aged CD-fed mice, AppNL-F was associated with larger in magnitude CA1 SR short- and long-term potentiation, without clear changes in basal transmission or plaque-free excitatory synapses.
This may suggest that synaptic strength is preserved in the presence of a toxic amyloid-β environment by enhancing synaptic plasticity (i.e. homeostatic plasticity).
HFD tended to reduce the AppNL-F-related LTP magnitude (P = 0.09), while clearly increasing excitatory synapse density in plaque-distant/free SR (P = 0.0001).
Trem2R47H had no effect on synaptic transmission, but increased synapse density (P = 0.02), possibly reflecting altered microglial regulation of removal of unhealthy synapses.
Overall, the data suggest that the possible homeostatic responses to amyloid-related dysfunction may be prevented by metabolic and genetic risk factors.
Extending the work by studying inhibitory synapse density (e.g. Bassoon-Gephyrin colocalisation).
Use electron microscopy to examine synaptic ultrastructure, including excitatory and inhibitory synapse types, active-zone structure, postsynaptic density size, and vesicle organisation.
Examining microglial-synapse interactions in plaque-distant regions and whether altered synapse density reflects changes in synaptic clearance
