IKK Deficiency in Myeloid Cells Ameliorates Alzheimer's Disease-Related Symptoms and Pathology

Alzheimer's disease (AD) is characterized by extracellular amyloid-beta (A beta) deposits and microglia-dominated inflammatory activation. Innate immune signaling controls microglial inflammatory activities and A beta clearance. However, studies examining innate immunity in A beta pathology and neuronal degeneration have produced conflicting results. In this study, we investigated the pathogenic role of innate immunity in AD by ablating a key signaling molecule, IKK beta, specifically in the myeloid cells of TgCRND8 APP-transgenic mice. Deficiency of IKK beta in myeloid cells, especially microglia, simultaneously reduced inflammatory activation andA beta load in the brain and these effects were associated with reduction of cognitive deficits and preservation of synaptic structure proteins. IKK beta deficiency enhanced microglial recruitment to A beta deposits and facilitated A beta internalization, perhaps by inhibiting TGF-beta-SMAD2/3 signaling, but did not affect A beta production and efflux. Therefore, inhibition of IKK beta signaling in myeloid cells improves cognitive functions in AD mice by reducing inflammatory activation and enhancing A beta clearance. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying AD progression

IKK beta Deficiency in Myeloid Cells Ameliorates Alzheimer's Disease-Related Symptoms and Pathology

Alzheimer's disease (AD) is characterized by extracellular amyloid-beta (A beta) deposits and microglia-dominated inflammatory activation. Innate immune signaling controls microglial inflammatory activities and A beta clearance. However, studies examining innate immunity in A beta pathology and neuronal degeneration have produced conflicting results. In this study, we investigated the pathogenic role of innate immunity in AD by ablating a key signaling molecule, IKK beta, specifically in the myeloid cells of TgCRND8 APP-transgenic mice. Deficiency of IKK beta in myeloid cells, especially microglia, simultaneously reduced inflammatory activation andA beta load in the brain and these effects were associated with reduction of cognitive deficits and preservation of synaptic structure proteins. IKK beta deficiency enhanced microglial recruitment to A beta deposits and facilitated A beta internalization, perhaps by inhibiting TGF-beta-SMAD2/3 signaling, but did not affect A beta production and efflux. Therefore, inhibition of IKK beta signaling in myeloid cells improves cognitive functions in AD mice by reducing inflammatory activation and enhancing A beta clearance. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying AD progression

Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease

Deficient energy metabolism and network hyperactivity are the early symptoms of Alzheimer's disease (AD). In this study, we show that administration of exogenous oxidative energy substrates (OES) corrects neuronal energy supply deficiency that reduces the amyloid-beta-induced abnormal neuronal activity in vitro and the epileptic phenotype in AD model in vivo. In vitro, acute application of protofibrillar amyloid-142 (A142) induced aberrant network activity in wild-type hippocampal slices that was underlain by depolarization of both the neuronal resting membrane potential and GABA-mediated current reversal potential. A142 also impaired synaptic function and long-term potentiation. These changes were paralleled by clear indications of impaired energy metabolism, as indicated by abnormal NAD(P)H signaling induced by network activity. However, when glucose was supplemented with OES pyruvate and 3-beta-hydroxybutyrate, A142 failed to induce detrimental changes in any of the above parameters. We administered the same OES as chronic supplementation to a standard diet to APPswe/PS1dE9 transgenic mice displaying AD-related epilepsy phenotype. In the ex-vivo slices, we found neuronal subpopulations with significantly depolarized resting and GABA-mediated current reversal potentials, mirroring abnormalities we observed under acute A1-42 application. Ex-vivo cortex of transgenic mice fed with standard diet displayed signs of impaired energy metabolism, such as abnormal NAD(P)H signaling and strongly reduced tolerance to hypoglycemia. Transgenic mice also possessed brain glycogen levels twofold lower than those of wild-type mice. However, none of the above neuronal and metabolic dysfunctions were observed in transgenic mice fed with the OES-enriched diet. In vivo, dietary OES supplementation abated neuronal hyperexcitability, as the frequency of both epileptiform discharges and spikes was strongly decreased in the APPswe/PS1dE9 mice placed on the diet. Altogether, our results suggest that early AD-related neuronal malfunctions underlying hyperexcitability and energy metabolism deficiency can be prevented by dietary supplementation with native energy substrates. Read the Editorial Highlight for this article on doi: 10.1111/jnc.12138.</p