The ketone body ß-hydroxybutyrate shifts microglial metabolism and suppresses amyloid-ß oligomer-induced inflammation in human microglia.

Fatty acids are metabolized by ß-oxidation within the "mitochondrial ketogenic pathway" (MKP) to generate ß-hydroxybutyrate (BHB), a ketone body. BHB can be generated by most cells but largely by hepatocytes following exercise, fasting, or ketogenic diet consumption. BHB has been shown to modulate systemic and brain inflammation; however, its direct effects on microglia have been little studied. We investigated the impact of BHB on Aß oligomer (AßO)-stimulated human iPS-derived microglia (hiMG), a model relevant to the pathogenesis of Alzheimer's disease (AD). HiMG responded to AßO with proinflammatory activation, which was mitigated by BHB at physiological concentrations of 0.1-2 mM. AßO stimulated glycolytic transcripts, suppressed genes in the ß-oxidation pathway, and induced over-expression of AD-relevant p46Shc, an endogenous inhibitor of thiolase, actions that are expected to suppress MKP. AßO also triggered mitochondrial Ca2+ increase, mitochondrial reactive oxygen species production, and activation of the mitochondrial permeability transition pore. BHB potently ameliorated all the above mitochondrial changes and rectified the MKP, resulting in reduced inflammasome activation and recovery of the phagocytotic function impaired by AßO. These results indicate that microglia MKP can be induced to modulate microglia immunometabolism, and that BHB can remedy "keto-deficiency" resulting from MKP suppression and shift microglia away from proinflammatory mitochondrial metabolism. These effects of BHB may contribute to the beneficial effects of ketogenic diet intervention in aged mice and in human subjects with mild AD.

Protective effects of diarylpropionitrile against hydrogen peroxide-induced damage in human neuroblastoma SH-SY5Y cells.

Oxidative stress is implicated in pathogenesis of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. The study demonstrates diarylpropionitrile (DPN), an antioxidant selective agonist of estrogen receptor ß, protected human neuroblastoma SH-SY5Y cells against H2O2-induced toxicity by attenuating production of reactive oxygen species, apoptosis, autophagy, NF-κB activation, MAPK p38, JNK and ERK 1/2 signaling pathways, and ß-site amyloid precursor protein cleaving enzyme level, but, interestingly, stimulating Akt pathway. These findings indicate the important potential of DPN to ameliorate oxidative stress-associated damage in neurodegenerative disorders.

Brain-derived neurotrophic factor increases cell number of neural progenitor cells derived from human induced pluripotent stem cells.

BACKGROUND: Several pieces of evidence from in vitro studies showed that brain-derived neurotrophic factor (BDNF) promotes proliferation and differentiation of neural stem/progenitor cells (NSCs) into neurons. Moreover, the JAK2 pathway was proposed to be associated with mouse NSC proliferation. BDNF could activate the STAT-3 pathway and induce proliferation in mouse NSCs. However, its effects on proliferation are not fully understood and JAK/STAT pathway was proposed to play a role in this activity. METHODS: In the present study, the effects of BDNF on cell proliferation and neurite outgrowth of Alzheimer's disease (AD) induced pluripotent stem cells (iPSCs)-derived human neural progenitor cells (hNPCs) were examined. Moreover, a specific signal transduction pathway important in cell proliferation was investigated using a JAK2 inhibitor (AG490) to clarify the role of that pathway. RESULTS: The proliferative effect of BDNF was remarkably observed as an increase in Ki-67 positive cells. The cell number of hNPCs was significantly increased after BDNF treatment represented by cellular metabolic activity of the cells measured by MTT assay. This noticeable effect was statistically shown at 20 ng/ml of BDNF treatment. BDNF, however, did not promote neurite outgrowth but increased neuronal cell number. It was found that AG490 suppressed hNPCs proliferation. However, this inhibitor partially decreased BDNF-induced hNPCs proliferation. These results demonstrated the potential role of BDNF for the amelioration of AD through the increase of AD-derived hNPCs number.

Neuroprotection of SAK3 on scopolamine-induced cholinergic dysfunction in human neuroblastoma SH-SY5Y cells.

Alzheimer's disease (AD) is the most common type of senile dementia. A number of factors have been proposed regarding pathology of AD, such as presence of ß-amyloid, and cholinergic and oxidative stress. SAK3 (ethyl 8'-methyl-2',5-dioxo-2-piperidin-1-ylspiro[cyclopentene-3,3'-imidazo[1,2-a]pyridine]-1-carboxylate) reduces ß-amyloid deposition and improves cognitive functions in amyloid precursor protein knock-in mice. Scopolamine is used to induce in cell lines a cholinergic deficit that mimics AD. In order to evaluate the possible neuroprotective properties of SAK3, human neuroblastoma SH-SY5Y cells were pretreated with the compound (25-100 nM) and further incubated in the presence of scopolamine (2 mM). SAK3 inhibited scopolamine-induced cellular apoptosis (morphologically and by determination of pro- and anti-apoptotic factor levels), increase in ROS levels, decrease in choline acetyltransferase level, phosphorylation of NF-κB, activation of Akt, JNK and p38 intracellular signaling pathways, and elevation of proinflammatory cytokines IL-1ß and IL-6, but not enhanced level of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). These results indicate SAK3 possessed protective properties against cholinergic deficit associated with anti-oxidant, anti-apoptotic and anti-inflammatory activities, suggesting that SAK3 might be a potential agent in the development of AD drug therapeutics.