MICROGLIA-MEDIATED TNFΑ SIGNALING ENABLES AΒ–DEPENDENT HOMEOSTATIC SYNAPTIC PLASTICITY

Amyloid-β (Aβ), a cleavage product of the Amyloid Precursor Protein (APP), is classically associated with Alzheimer’s disease and synaptic dysfunction. Nonetheless, Aβ peptides of various lengths are present in the CSF of healthy individuals, and recent evidence indicates a physiological role for full-length Aβ1-42 in homeostatic synaptic plasticity. The cellular and molecular mechanisms underlying this effect remain incompletely understood. To dissect the underlying mechanism, we performed whole-cell patch-clamp recordings from dentate gyrus granule cells in organotypic entorhino-hippocampal tissue cultures derived from wild-type and APP-knockout mice, combined with immunohistochemical and biochemical methods. We tested whether the homeostatic effects of physiological Aβ are mediated by defined Aβ-derived domains and assessed the contribution of microglia and the microglia-associated cytokine TNFα. Using slice cultures from wild-type and APP-deficient mice, we found that a low–molecular mass Aβ domain restores TTX-induced homeostatic scaling in APP-deficient cultures, whereas a higher–molecular mass domain did not. Notably, this rescue effect was abolished upon microglia depletion, indicating that microglia are required for Aβ-dependent homeostatic synaptic plasticity. Furthermore, exogenous TNFα was sufficient to reinstate TTX-induced homeostatic synaptic scaling in APP-deficient cultures. Together, these findings identify microglia as an essential cellular mediator of physiological Aβ signaling in homeostatic synaptic plasticity and establish TNFα as a critical downstream effector. Our data support a microglia-dependent mechanism by which defined Aβ domains contribute to the maintenance of synaptic stability under conditions of altered network activity.