Significance: Although both patients with Alzheimer’s disease (AD) and mouse models of the disease suffer from a profound neuronal hyperactivity mediating an impairment of memory and cognition, the underlying mechanisms remain elusive. Here, we show that neuronal hyperactivity is a hallmark of healthy aging but is further aggravated by AD-related mutations in presenilin 1 protein. AD-mediated enhancement of neuronal hyperactivity occurred even in the absence of amyloid plaques and neuroinflammation, mainly due to a presenilin-mediated dysfunction of intracellular Ca ²⁺ stores in presynaptic boutons, likely causing more frequent activation of synaptic NMDA receptors. Emptying the stores normalized neuronal network activity in mutant mice, thus identifying presynaptic Ca ²⁺ stores as a key element controlling AD-related neuronal hyperactivity and as a target for disease-modifying treatments.

Aquaporin‐4 (AQP4), the principal water channel in astrocytes, is involved in brain water movement, inflammation, and neuroexcitation. In this study, there was strong neuroprotection in mice lacking AQP4 in a model of global cerebral ischemia produced by transient, bilateral carotid artery occlusion (BCAO). Survival and neurological outcome were greatly improved in the AQP4 ^‐/‐ vs. AQP4 ^+/+ mice after occlusion, with large and robust differences in both outbred (CD1) and inbred (C57bl/6) mouse strains without or with mechanical ventilation. Improved survival was also seen in mice lacking the scaffold protein α‐syntrophin, which manifest reduced astrocyte water permeability secondary to defective AQP4 plasma membrane targeting. Intracranial pressure elevation and brain water accumulation were much reduced in the AQP4 ^‐/‐ vs. AQP4 ^+/+ mice after carotid artery occlusion, as were blood–brain barrier (BBB) disruption and neuronal loss. Brain slices from AQP4 ^‐/‐ mice showed significantly reduced cell swelling and cytotoxicity in response to oxygen–glucose deprivation, compared with slices from AQP4 ^+/+ mice. Our findings suggest that the neuroprotective effect of AQP4 deletion in global cerebral ischemia involves reduced astrocyte swelling and brain water accumulation, resulting in reduced BBB disruption, inflammation, and neuron death. AQP4 water transport inhibition may improve survival and neurological outcome after cardiac arrest and in other conditions associated with global cerebral ischemia.—Katada, R., Akdemir, G., Asavapanumas, N., Ratelade, J., Zhang, H., Verkman, A. S. Greatly improved survival and neuroprotection in aquaporin‐4 knockout mice following global cerebral ischemia. FASEB J. 28, 705–714 (2014). www.fasebj.org

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system caused by binding of pathogenic IgG autoantibodies (NMO-IgG) to astrocyte water channel aquaporin-4 (AQP4). Astrocyte damage and downstream inflammation require NMO-IgG effector function to initiate complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we evaluated the potential therapeutic utility of the bacterial enzyme IdeS (IgG-degrading enzyme of Streptococcus pyogenes), which selectively cleaves IgG antibodies to yield Fc and F(ab′)₂ fragments. In AQP4-expressing cell cultures, IdeS treatment of monoclonal NMO-IgGs and NMO patient sera abolished CDC and ADCC, even when IdeS was added after NMO-IgG was bound to AQP4. Binding of NMO-IgG to AQP4 was similar to that of the NMO-F(ab′)₂ generated by IdeS cleavage. NMO-F(ab′)₂ competitively displaced pathogenic NMO-IgG, preventing cytotoxicity, and the Fc fragments generated by IdeS cleavage reduced CDC and ADCC. IdeS efficiently cleaved NMO-IgG in mice in vivo, and greatly reduced NMO lesions in mice administered NMO-IgG and human complement. IgG-selective cleavage by IdeS thus neutralizes NMO-IgG pathogenicity, and yields therapeutic F(ab′)₂ and Fc fragments. IdeS treatment, by therapeutic apheresis or direct administration, may be beneficial in NMO.