Assessment of the effects of plaques and glia on synaptic transmission in APP knock-in models of Alzheimer's disease" and I have attached an updated s

Alzheimer's disease (AD) is a neurodegenerative disorder associated with the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles, coupled to extensive synaptic denervation and gliosis. The role of microglia in disease progression has become a central focus for AD research. Studies in AD mouse models have demonstrated that microglia cluster around amyloid plaques, with some indications that plaque-associated microglia phagocytose synapses in these regions. The present work aimed to explore if these microglia phagocytose damaged synapses as a protective mechanism to limit plaque-associated toxicity. Here, the hippocampus of APPNL-F and APPNL-G-F was examined using patch-clamp electrophysiology and immunohistochemistry. This work also explored APPNL-F/TREM2R47H mice to determine how compromised microglial response affects synaptic activity.
Here, individual CA3 axons were stimulated and postsynaptic CA1 cells were recorded from using a patch-clamp setup. Post-hoc imaging was used to determine if plaques were present around the axon stimulation site, deeming a recording as "plaque" or "no-plaque." Experiments were performed in 4-5- and 7-9-month-old APPNL-G-F mice to determine the effects of plaques on synaptic transmission. Age-related changes were observed in rise times and postsynaptic amplitudes only in no-plaque conditions, indicating plaque-specific effects on postsynaptic activity. APPNL-G-F mice also showed increased microglial density and age-related reductions in astrocyte density.
APPNL-F/TREM2R47H mice were also explored to determine the effects of perturbed microglial response on synaptic activity. Both APPNL-F and APPNL-F/TREM2R47H mice showed increased glutamate release in plaque conditions. Reductions in postsynaptic amplitudes in plaque conditions were found only in APPNL-F mice, showing the necessity for microglia to observe these effects. APPNL-F/TREM2R47H exhibited reduced microglial density and higher plaque load than APPNL-F mice.
Altogether, the results of this study illustrate the dual effects of plaque presence around axons which are driven by the effects of soluble Ab and microglia on the presynapse and postsynapse, respectively.