A cholesterol-coupled N-acetyl-aspartyl-glutamate metabolic network facilitates the neuroprotective impact of estradiol in neurons

Abstract Sex differences have been demonstrated in Alzheimer's disease (AD), yet the intrinsic cellular changes underlying the enhanced disease vulnerability observed in postmenopausal women remain elusive. We demonstrate that sustained loss of peripheral estradiol is correlated with accelerated cognitive and memory decline. The resulting brain transcriptomic and metabolomic changes suggest the impairment of ERRα. Estradiol supports ERRα activity via its actions on neuronal cholesterol homeostasis. Consequently, this prevents truncation of the TCA cycle at succinate dehydrogenase, which would otherwise cause a net catabolic shift of N-acetyl-aspartyl-glutamate (NAAG), driven by an adaptive aspartate-dependent response that attempts to reconstruct a “mini-cycle”. The free glutamate released alongside the net catabolism of NAAG is stochastically released presynaptically, thereby increasing spontaneous neuronal activities. Coupled with the bioenergetic incompetency that occurs during estradiol-loss, this slowly depletes cellular ATP and increases susceptibility to energy crises triggered by additional excitatory insults, ultimately contributing to the female-biased vulnerability to AD.