The overall effect of brain zinc (Zn2+) in the progression and development of Alzheimer's disease (AD) is still not completely understood. Although an excess of Zn2+ can exacerbate the pathological features of AD, a deficit of Zn2+ intake has also been shown to increase the volume of amyloid plaques in AD transgenic mice. In this study, we investigated the effect of dietary Zn2+ supplementation (30 p.p.m.) in a transgenic mouse model of AD, the 3xTg-AD, that expresses both β amyloid (Aβ)- and tau-dependent pathology. We found that Zn2+ supplementation greatly delays hippocampal-dependent memory deficits and strongly reduces both Aβ and tau pathology in the hippocampus. We also evaluated signs of mitochondrial dysfunction and found that Zn2+ supplementation prevents the age-dependent respiratory deficits we observed in untreated 3xTg-AD mice. Finally, we found that Zn2+ supplementation greatly increases the levels of brain-derived neurotrophic factor (BDNF) of treated 3xTg-AD mice. In summary, our data support the idea that controlling the brain Zn2+ homeostasis may be beneficial in the treatment of AD.

The triple-transgenic Alzheimer (3 × Tg-AD) mouse expresses mutant PS1M146V, APPswe, and tauP301L transgenes and progressively develops plaques and neurofibrillary tangles with a temporal- and region-specific profile that resembles the neuropathological progression of Alzheimer's disease (AD). In this study, we used proteomic approaches such as two-dimensional gel electrophoresis and mass spectrometry to investigate the alterations in protein expression occurring in the brain and cerebellum of 3 × Tg-AD and presenilin-1 (PS1) knock-in mice (animals that do not develop Aβ- or tau-dependent pathology nor cognitive decline and were used as control). Finally, using the Ingenuity Pathway Analysis we evaluated novel networks and molecular pathways involved in this AD model. We identified several differentially expressed spots and analysis of 3 × Tg-AD brains showed a significant downregulation of synaptic proteins that are involved in neurotransmitter synthesis, storage and release, as well as a set of proteins that are associated with cytoskeleton assembly and energy metabolism. Interestingly, in the cerebellum, a structure not affected by AD, we found an upregulation of proteins involved in carbohydrate metabolism and protein catabolism. Our findings help to unravel the pathogenic brain mechanisms set in motion by mutant amyloid precursor protein (APP) and hyperphosphorylated tau. These data also reveal cerebellar pathways that may be important to counteract the pathogenic actions of Aβ and tau, and ultimately offer novel targets for therapeutic intervention.

]i increases induced by T2 and T3. In the presence of extracellular calcium (1.2 mM), under carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, T2 and T3 increased both [Ca 2ϩ ]i and intracellular Na ϩ concentration; nimodipine reduced the [Ca 2ϩ ]i increases elicited by T2 and T3, but inhibition of NO synthase and blockade of the Na ϩ /H ϩ pump by 5-(N-ethyl-N-isopropyl)amiloride prevented only that elicited by T3; and CB-DMB, bisindolylmaleimide, and LY-294002 (inhibitors of the Na ϩ /Ca 2ϩ exchanger, PKC, and phosphatidylinositol 3-kinase, respectively) failed to modify the T2-and T3-induced effects. Collectively, the present results suggest that T2 and T3 exert short-term nongenomic effects on intracellular calcium and NO by modulating plasma membrane and mitochondrial pathways that differ between these iodothyronines. thyroid hormones; mitochondria; calcium; nitric oxide THYROID HORMONES (thyroxine, T4; triiodothyronine, T3) play important roles in cellular development, growth, and metabolism, mainly through the interaction of T3 with nuclear receptors (38). In addition, short-term, nongenomic actions of thyroid hormones have been reported to occur at the level of the plasma membrane, channels and pumps, cytoskeleton, cytoplasm, and organelles in mammalian cells (for review, see Ref. 16 and references therein) (15,17,33,48,51). Some of these actions lead rapidly to posttranslational modifications of nucleoproteins, including MAPK-mediated serine phosphorylation of the thyroid hormone receptor (13), estrogen receptor (52), and p53 (49). In addition, upstream of MAPK, PKC and phosphatidylinositol 3-kinase (PI3-K) pathways may also be activated by thyroid hormones (42).These rapid events seem to imply the existence of membrane receptors for thyroid hormones linked to signal-transduction pathways that are not yet well characterized. Indeed, membrane binding sites for T3 have been identified in human and rat erythrocytes (9, 2), rat hepatocytes (28, 40), and pituitary cells (25), and Bergh and colleagues (7) have identified integrin-␣V␤3 as a plasma membrane thyroid hormone binding site.In addition to T3, other iodothyronines, such as 3,5-diiodo-L-thyronine (T2), a naturally occurring iodothyronine, display biological activities. Indeed, it has been shown that T2 exerts short-term effects on both resting metabolic rate and mitochondrial activities (29), essentially by a nuclearindependent pathway (for review, see Ref. 35 and references therein). In previous studies, it has been suggested that T2, as well as T3, may influence cellular energy metabolism and cell differentiation by modulating ion pathways (27,36,47). In particular, T3 can induce a redistribution of calcium across plasma and mitochondrial membranes, thereby affecting energy metabolism (27,36). Although a role for calcium has been proposed in the mediation of the nongenomic effects triggered by iodothyronines, the underlying biochemical pathways are not yet fully established.In the present study, in pituitary GH 3 cells, we explored 1) the modu...

Chronic exposure to polychlorinated biphenyls (PCBs), ubiquitous environmental contaminants, can adversely affect the development and function of the nervous system. Here we evaluated the effect of PCB exposure on mitochondrial function using the PCB mixture Aroclor-1254 (A1254) in SH-SY5Y neuroblastoma cells. A 6-hour exposure to A1254 (5 μg/ml) reduced cellular ATP production by 45%±7, and mitochondrial membrane potential, detected by TMRE, by 49%±7. Consistently, A1254 significantly decreased oxidative phosphorylation and aerobic glycolysis measured by extracellular flux analyzer. Furthermore, the activity of mitochondrial protein complexes I, II, and IV, but not V (ATPase), measured by BN-PAGE technique, was significantly reduced after 6-hour exposure to A1254. The addition of pyruvic acid during exposure to A1254 significantly prevent A1254-induced cell injury, restoring resting mitochondrial membrane potential, ATP levels, oxidative phosphorylation and aerobic glycolysis. Furthermore, pyruvic acid significantly preserved the activity of mitochondrial complexes I, II and IV and increased basal activity of complex V. Collectively, the present results indicate that the neurotoxicity of A1254 depends on the impairment of oxidative phosphorylation, aerobic glycolysis, and mitochondrial complexes I, II, and IV activity and it was counteracted by pyruvic acid.