| 2 | Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology显示文摘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 Aβplaques,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. | Ankit Verma Anna Shteinfer-Kuzmine Nikita Kamenetsky Srinivas Pittala Avijit Paul Edna Nahon Crystal Alberto Ouro Vered Chalifa-Caspi Swaroop Kumar Pandey Alon Monsonego Noga Vardi Shira Knafo Varda Shoshan-Barmatz | 2022 | Translational Neurodegeneration2022，11，1： | 0 |
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