Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology

Abstract Background Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca2+ homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction. Methods To address the multiple pathways involved in AD, neuronal cultures and a 5 × FAD mouse model of AD were treated with VBIT-4. We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting, immunofluorescence, q-RT-PCR, 3-D structural analysis and several behavioral tests. Results In neuronal cultures, amyloid-beta (Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4. Using an AD-like 5 × FAD mouse model, we showed that VDAC1 was overexpressed in neurons surrounding Aβ plaques, but not in astrocytes and microglia, and this was associated with neuronal cell death. VBIT-4 prevented the associated pathophysiological changes including neuronal cell death, neuroinflammation, and neuro-metabolic dysfunctions. VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype. Moreover, VBIT-4 prevented cognitive decline in the 5 × FAD mice as evaluated using several behavioral assessments of cognitive function. Interestingly, VBIT-4 protected against AD pathology, with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque load. Conclusions The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention, and VBIT-4 is a promising drug candidate for AD treatment

Chromium spinel in Late Quaternary volcanic rocks from Kamchatka: Implications for spatial compositional variability of subarc mantle and its oxidation state

Highlights • First comprehensive dataset of spinel inclusions in high-Mg olivine from Kamchatka • Oxidation state of parental magmas of Kamchatka ranging from ΔQFM+0.7 to +3.7 • ΔQFM correlates with Ba/La and La/Nb for back-arc magmas of Kamchatka • Decoupling of Cr# and TiO2 in primitive Cr-Spinel suggests slab melt contribution Abstract The Kamchatka volcanic arc (Russia) is one of well-studied but complex tectonic margins on Earth, with an extensive geologic history stretching as far back as the Late Cretaceous. Unlike many other subduction zones, primitive basalts with Mg# > 65 are abundant in Kamchatka, thereby allowing characterization of the mantle source through compositional analyses of near-liquidus minerals in the rocks. In this paper, we present a comprehensive dataset on the composition of Cr-spinel inclusions in olivine for all main Late Quaternary volcanic zones in Kamchatka, comprising of analyses of 1604 spinel inclusions and their host-olivine from 104 samples representing 30 volcanoes and volcanic fields. The studied rocks are basalts, basaltic andesites and high-Mg andesites, which cover the whole compositional range the Late Quaternary primitive volcanic rocks in Kamchatka. The composition of spinel shows large variability. Spinel inclusions with the lowest Cr# and Fe3+/Fe2+ ratios were found in basalts from Sredinny Range and Northern Kamchatka, whereas the most Cr-rich and oxidized spinel inclusions occur in basalts and high-Mg andesites from the Central Kamchatka Depression. Intermediate Cr-spinel compositions characterize the Eastern Volcanic Belt of Kamchatka. The compositions of olivine-spinel pairs were used to quantify the oxidation state of parental Kamchatka magmas and the degree of partial mantle melting. The redox conditions recorded in spinel compositions range from ΔQFM = +0.7 to +3.7. ΔQFM for samples from the Sredinny Range and Northern Kamchatka correlates with a number of proxies of the involvement of slab-derived components incorporated in the composition of their host-rocks (e.g., La/Nb and Ba/La), which suggests a coupling between the mantle oxidation and metasomatism by slab-derived fluids or melts. These correlations were not observed for frontal Kamchatka volcanoes with the highest estimated ΔQFM, which possibly indicates a buffering of the mantle oxidation state by sulfur. The estimated degrees of partial mantle melting range from 8 to >20% for Kamchatka volcanoes. Spinel from the Central Kamchatka Depression has the highest Cr# and could crystallize from magmas generated from the most depleted sources. In contrast to the Eastern Volcanic Belt, spinel Cr# and the inferred degrees of melting in the Central Kamchatka Depression do not correlate with spinel TiO2 content. The apparent decoupling between the proxies of mantle depletion in the CKD spinel is interpreted to reflect refertilization of the CKD mantle by oxidized Ti-rich slab- or mantle lithosphere-derived melts near the northern edge of the subducting Pacific Plate. This study demonstrates that the composition of Cr-spinel in volcanic rocks in combination with bulk-rock compositions can be a powerful tool to map regional variations of the mantle source depletion, oxidation state, and involvement of various slab derived components in island-arc magmatism

Constraints on mantle melting and composition and nature of slab components in volcanic arcs from volatiles (H₂O, S, Cl, F) and trace elements in melt inclusions from the Kamchatka Arc

New and published data on the composition of melt inclusions in olivine (Fo73–91) from volcanoes of the Kamchatka and northern Kurile Arc are used 1) to evaluate the combined systematics of volatiles (H2O, S, Cl, F) and incompatible trace elements in their parental magmas and mantle sources, 2) to constrain thermal conditions of mantle melting, and 3) to estimate the composition of slab-derived components. We demonstrate that typical Kamchatkan arc-type magmas originate through 5–14% melting of sources similar or slightly more depleted in HFSE (with up to ∼ 1 wt.% previous melt extraction) compared to MORB-source mantle, but strongly enriched in H2O, B, Be, Li, Cl, F, LILE, LREE, Th and U. Mean H2O in parental melts (1.8–2.6 wt.%) decreases with increasing depth to the subducting slab and correlates negatively with both ‘fluid-immobile’ (e.g. Ti, Na, LREE) and most ‘fluid-mobile’ (e.g. LILE, S, Cl, F) incompatible elements, implying that solubility in hydrous fluids or amount of water does not directly control the abundance of ‘fluid-mobile’ incompatible elements. Strong correlation is observed between H2O/Ce and B/Zr (or B/LREE) ratios. Both, calculated H2O in mantle sources (0.1–0.4%) and degrees of melting (5–14%) decrease with increasing depth to the slab indicating that the ultimate source of water in the sub-arc mantle is the subducting oceanic plate and that water flux (together with mantle temperature) governs the extent of mantle melting beneath Kamchatka. A parameterized hydrous melting model [Katz et al. 2003, G3, 4(9), 1073] is utilized to estimate that mantle melting beneath Kamchatka occurs at or below the dry peridotite solidus (1245–1330 °C at 1.5–2.0 GPa). Relatively high mantle temperatures (yet lower than beneath back-arc basins and ocean ridges) suggest substantial corner flow driven mantle upwelling beneath Kamchatka in agreement with numerical models implying non-isoviscous mantle wedge rheology. Data from Kamchatka, Mexico and Central America indicate that < 5% melting would take place beneath continental arcs without water flux from the subducting slab. A broad negative correlation appears to exist between crustal thickness and the temperature of magma generation beneath volcanic arcs with larger amounts of decompression melting occurring beneath thinner arc crust (lithosphere). In agreement with the high mantle temperatures, we observe a systematic change in the composition of slab components with increasing slab depth from solute-poor hydrous fluid beneath the volcanic front to solute-rich hydrous melt or supercritical liquid at deeper depths beneath the rear arc. The solute-rich slab component dominates the budget of LILE, LREE, Th and U in the magmas and originates through wet-melting of subducted sediments and/or altered oceanic crust at ≥ 120 km depth. Melting of the upper parts of subducting plates under water flux from deeper lithosphere (e.g. serpentinites), combined with high temperatures in the mantle wedge, may be a more common process beneath volcanic arcs than has been previously recognized