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

Abstract

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 have direct clinical implications for Alzheimer's disease: it supports therapeutic strategies aimed at preserving or restoring physiological Aβ42 levels rather than reducing them.