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

引用

Translational Neurodegeneration 2022年第1期11卷 1-30页

作者： 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 Department of Life Sciences Ben-Gurion University of the Negev84105 Beer-ShevaIsrael National Institute for Biotechnology in the Negev Ben-Gurion University of the Negev84105 Beer-ShevaIsrael Achva Academic College 79804 ShikmimIsrael Department of Physiology Faculty of Health SciencesBen-Gurion University of the Negev84105 Beer-ShevaIsrael Ilse Katz Institute for Nanoscale Science and Technology Ben-Gurion University of the Negev84105 Beer-ShevaIsrael The Shraga Segal Department of Microbiology Immunologyand GeneticsFaculty of Health SciencesBen-Gurion University of the Negev84105 Beer-ShevaIsrael NeuroAging Group(NEURAL) Clinical Neurosciences Research Laboratory(LINC)Health Research Institute of Santiago de Compostela(IDIS)15706 Santiago de CompostelaSpain.

Background Alzheimer’s disease(AD)exhibits mitochondrial dysfunctions associated with dysregulated metabolism,brain inflammation,synaptic loss,and neuronal cell *** 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 ***,we targeted VDAC1 with VBIT-4,a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity,and mitochondria *** To address the multiple pathways involved in AD,neuronal cultures and a 5×FAD mouse model of AD were treated with *** addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting,immunofluorescence,q-RT-PCR,3-D structural analysis and several behavioral *** In neuronal cultures,amyloid-beta(Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by *** 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 ***-4 prevented the associated pathophysiological changes including neuronal cell death,neuroinflammation,and neuro-metabolic ***-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective ***,VBIT-4 prevented cognitive decline in the 5×FAD mice as evaluated using several behavioral assessments of cognitive ***,VBIT-4 protected against AD pathology,with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque *** 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.

关键词： Alzheimer’s disease Metabolism Mitochondria Neuroinflammation VDAC1

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