Fig. 10

Schematic model of mitochondria and VDAC1 functions in apoptosis, inflammasome activation, and inflammatory response leading to AD, and their prevention by VBIT-4 in 5 × FAD mice. a Aβ plaques contain neurons that overexpress VDAC1 (red circles), astrocytes (green cells), and activated microglia (yellow cells). Following VBIT-4 treatment, the cells undergo metabolic reprograming to OXPHOS and restored mitochondria functions; inhibited apoptosis and inflammation, leading to neuronal survival and improved astrocyte and microglia morphology and their activation to the neuroprotective phenotypes. All lead to modulated neuronal survival on and improved cognitive function. b Molecular mechanisms proposed for mitochondria and VDAC1-mediated AD pathology and their modulation by VBIT-4. VDAC1 is involved in numerous mitochondria-associated functions, including cell metabolism, inflammation, and apoptosis, which are all impaired in AD. VDAC1 overexpression induced by Aβ triggers mitochondrial dysfunction, apoptosis, and immuno-inflammation via three major signaling pathways: I. Apoptosis pathway (blue arrows): Apoptosis is induced by oligomerization of the overexpressed VDAC1 (induced by Aβ) to form a large channel mediating Cyto c release, apoptosome formation, caspase-3 activation, and apoptotic cell death, contributing to AD. VBIT-4 inhibits VDAC1 oligomerzation, thereby apoptosis. II. Mitochondrial signaling (green arrows): Mitochondrial dysfunction (resulting from Aβ toxicity) increases ROS levels, as well as expression of HK-I, pro-caspase-1, Ca²⁺ and TSPO. This facilitates the NRLP3 inflammasome assembly and activation, leading to pro-caspase-1 activation and pro-inflammatory cytokine maturation, thereby initiating an inflammatory cascade associated with AD development. VBIT-4 prevents mitochondrial dysfunction, and thereby the mitochondria signaling to inflammasome activation. III. Impaired metabolism (orange arrows): Mitochondria decreased metabolism, connected to epigenetic, alters gene expression [141], increasing NF-kB levels, thereby enhancing inflammatory factor levels associated with neuroinflammation. These, together with Aβ inducing VDAC1 and p53 expression stimulating apoptosis [54,55,56], lead to AD development. VBIT-4 increases the expression of IL-4 and TGF-β, suppressing NLRP3-dependent caspase-1 activation. In this model, the overexpression and oligomerization of VDAC1 acts as a common functional junction for all these activated pathways in AD. Hence, inhibition of VDAC1 oligomerization by VBIT-4 suppresses apoptosis while restoring metabolism and suppressing NLRP3-dependent caspase-1 activation and the subsequent IL-1β and TNF-α activation, resulting in inhibition of inflammation. VBIT-4 inhibits mtDNA release into the cytosol, and thereby NLRP3 activation and IL-1β production. In addition, VBIT-4 upregulates IL-4 and TGF-β to modulate neuroprotective phenotypes of astrocytes and microglia. Collectively, these effects of VBIT-4 lead to prevention of AD pathology including cognitive dysfunction