Alzheimer's disease (AD) is the most common reason for elderly dementia in the world. We proposed that memory loss in AD is related to destabilization of mushroom postsynaptic spines involved in long-term memory storage. We demonstrated previously that stromal interaction molecule 2 (STIM2)-regulated neuronal store-operated calcium entry (nSOC) in postsynaptic spines play a key role in stability of mushroom spines by maintaining activity of synaptic Ca

Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and Alzheimer's disease (AD). The stability of mushroom spines depends on stromal interaction molecule 2 (STIM2)-mediated neuronal-store-operated Ca 2ϩ influx (nSOC) pathway, which is compromised in AD mouse models, in aging neurons, and in sporadic AD patients. Here, we demonstrate that the Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 channels form a STIM2-regulated nSOC Ca 2ϩ channel complex in hippocampal mushroom spines. We further demonstrate that a known TRPC6 activator, hyperforin, and a novel nSOC positive modulator, NSN21778 (NSN), can stimulate activity of nSOC pathway in the spines and rescue mushroom spine loss in both presenilin and APP knock-in mouse models of AD. We further show that NSN rescues hippocampal long-term potentiation impairment in APP knock-in mouse model. We conclude that the STIM2-regulated TRPC6/Orai2 nSOC channel complex in dendritic mushroom spines is a new therapeutic target for the treatment of memory loss in aging and AD and that NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.

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This article is available online at http://www.jlr.org but unlike VA, which is stored in tissues as retinyl ester (RE) and mobilized to produce RA ( 4 ), no signifi cant amount of RA is stored and the pool of RA turns over rapidly ( 5 ). RA and other retinoids have been shown to enhance alveolar septation in neonatal rats and mice (as reviewed in Refs. 2,3,6,7 ) and in some cases to improve lung repair after injury in adults ( 3,8,9 ). Most of the VA present in the lungs is in the form of RE ( 10-12 ). In fullterm infants, a process of signifi cant RE accumulation in the lungs has begun from the third trimester of fetal life, after which the stored RE becomes quickly depleted during late gestation and early postnatal life ( 10 ). By contrast, preterm infants often have low VA status at birth ( 13-15 ), which may contribute to poor lung maturation and increased susceptibility to respiratory diseases ( 16 ). Therefore, ways to improve RE storage in the lungs in the postnatal period could be useful clinically for supporting retinoid-requiring metabolic functions and aiding postnatal lung development.Previously, we tested a combination of VA (retinol) and RA, referred to as VARA (10:1 molar mixture of VA and RA) as an oral supplement for promoting lung RE formation ( 12 ). Lung RE increased synergistically, at least 4-fold more than for an equal amount of VA alone ( 17 ). As RA is not reduced to retinol in vivo and thus is not a substrate for tissue RE synthesis, the increase in RE in the lungs implies that RA plays a regulatory role in this organ, in some manner facilitating RE formation. The synergistic effect of VARA was selective for the lungs, as RE formation in the liver did not differ between VARA and an equal dose of VA only ( 12,17 ). In a metabolic study using [ 3 H]retinol to trace the uptake of newly absorbed retinol, we found that RA served to direct more of the [ 3 H]retinol tracer and, thus, the oral VA supplement, into the neonatal lung ( 12 ).Abstract Vitamin A (VA) is essential for fetal lung development and postnatal lung maturation. VA is stored mainly as retinyl esters (REs), which may be mobilized for production of retinoic acid (RA). This study was designed 1 ) to evaluate several acidic retinoids for their potential to increase RE in the lungs of VA-supplemented neonatal rats, and 2 ) to determine the expression of retinoid homeostatic genes related to retinol uptake, esterifi cation, and catabolism as possible mechanisms. When neonatal rats were treated with VA combined with any one of several acidic retinoids (RA, 9-cis -RA, or Am580, a stable analog of RA), lung RE increased ‫ف‬ 5-7 times more than after an equal amount of VA alone. Retinol uptake and esterifi cation during the period of absorption correlated with increased expression of both STRA6 (retinol-binding protein receptor) and LRAT (retinol esterifi cation), while a reduction in RE after 12 h in Am580-treated, VA-supplemented rats correlated with a strong and persistent increase in CYP26B1 (RA hydroxylase). We conclude that neona...

Magnesium-based implants have been shown to influence the surrounding bone structure. In an attempt to partially reveal the cellular mechanisms involved in the remodelling of magnesium-based implants, the influence of increased extracellular magnesium content on human osteoclasts was studied. Peripheral blood mononuclear cells were driven towards an osteoclastogenesis pathway via stimulation with receptor activator of nuclear factor kappa-B ligand and macrophage colony-stimulating factor for 28 days. Concomitantly, the cultures were exposed to variable magnesium concentrations (from either magnesium chloride or magnesium extracts). Osteoclast proliferation and differentiation were evaluated based on cell metabolic activity, total protein content, tartrate-resistant acid phosphatase activity, cathepsin K and calcitonin receptor immunocytochemistry, and cellular ability to form resorption pits. While magnesium chloride first enhanced and then opposed cell proliferation and differentiation in a concentration-dependent manner (peaking between 10 and 15mM magnesium chloride), magnesium extracts (with lower magnesium contents) appeared to decrease cell metabolic activity (≈50% decrease at day 28) while increasing osteoclast activity at a lower concentration (twofold higher). Together, the results indicated that (i) variations in the in vitro extracellular magnesium concentration affect osteoclast metabolism and (ii) magnesium extracts should be used preferentially in vitro to more closely mimic the in vivo environment.