Activity-dependent glucose uptake in the mouse prefrontal cortex depends on endogenous beta-amyloid production

Beta-amyloid (Aβ) is continuously produced in the healthy brain as soluble monomers, yet its physiological function has remained largely unexplored compared to the well-studied toxic aggregates in Alzheimer's disease. We previously showed that depolarization-induced release of endogenous Aβ enhances glucose uptake in rodent cultured cortical neurons, an effect recapitulated by synthetic human Aβ₄₂ monomers added to neurons upon glucose restoration after deprivation. To investigate whether this mechanism operates in vivo, we used memantine to transiently increase network activity in the prefrontal cortex of living mice. Memantine is known to disinhibit prefrontal cortex circuits by preferentially blocking NMDA receptors on GABAergic interneurons. In cultured cortical neurons, a brief challenge with memantine (10 μM) activated neuronal energy metabolism-glucose uptake and lactate release-through a γ-secretase-dependent mechanism. In the mouse prefrontal cortex, systemic memantine (20 mg/kg) increased 2-deoxyglucose uptake and concurrently enhanced γ-secretase activity and elevated soluble Aβ₄₂ levels. Pre-treatment with the γ-secretase inhibitor DAPT (100 mg/kg) or with the selective Aβ₄₂-lowering modulator JNJ-40418677 (80 mg/kg) prevented memantine-induced glucose uptake and reduced the memantine-induced increase in soluble Aβ₄₂, demonstrating that acute Aβ₄₂ production was required for activity-dependent glucose uptake in the mouse prefrontal cortex. This work establishes Aβ₄₂ as a physiological neurometabolic coupler in the prefrontal cortex and has direct clinical implications for Alzheimer's disease: it supports therapeutic strategies aimed at preserving or restoring physiological Aβ₄₂ levels rather than reducing them.