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.

Ablation of GPR56 Causes β-Cell Dysfunction by ATP Loss through Mistargeting of Mitochondrial VDAC1 to the Plasma Membrane

“…VDAC1 upregulation and oligomerization is caused by oxidative and nitrosative stress, not only in β-cells in T2D but also in neurodegenerative diseases, in particular, Alzheimer’s disease [ 47 , 48 ]. It is, therefore, of great interest that VBIT-4, which inhibits VDAC1 conductance and oligomerization, prevents onset of diabetes in db/db mice [ 14 ] and markedly improves the phenotype in a mouse model of Alzheimer’s disease [ 48 ].…”

“…VDAC1 upregulation and oligomerization is caused by oxidative and nitrosative stress, not only in β-cells in T2D but also in neurodegenerative diseases, in particular, Alzheimer’s disease [ 47 , 48 ]. It is, therefore, of great interest that VBIT-4, which inhibits VDAC1 conductance and oligomerization, prevents onset of diabetes in db/db mice [ 14 ] and markedly improves the phenotype in a mouse model of Alzheimer’s disease [ 48 ]. VBIT-4, thus, has both acute effects on cell signaling by preventing ATP loss through VDAC1 expressed in the plasma membrane and long-term actions on gene expression and cell function in diseases linked to oxidative stress and mitochondrial dysfunction.…”

Apoptotic proteins with non-apoptotic activity: expression and function in cancer

“…Although VDAC1 overexpression is associated with apoptosis [ 17 ], it is somewhat unexpectedly also overexpressed in cancers [ 17 , 36 , 45 , 48 – 50 ], as well as in other pathologies [ 36 ] such as Alzheimer’s disease [ 51 – 54 ], in β-cells in type 2 diabetes [ 55 ], and in autoimmune diseases such as lupus [ 24 ], inflammatory bowel diseases [ 56 ], non-alcoholic steatohepatitis [ 57 ], acute liver injury [ 58 ], rheumatoid arthritis [ 59 ] cardiovascular diseases [ 60 ], and in the T cells of COVID-19 patients [ 61 ].…”

“…This apparent paradox may be explained by the finding that, while inhibition of apoptosis may lead to cancer and other severe disorders [ 62 ], activation of apoptosis may cause neurodegenerative and [ 54 ] autoimmune diseases [ 24 , 56 ]. The latter can be targeted by inhibiting VDAC1 oligomerization, and thereby apoptosis [ 31 , 52 ].…”

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

“…Following publication of this article [ 1 ], the authors identified an error in the family name of Alon Monsonego.…”