Browsing by Author "Du, Heng"
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Item Amyloid Beta-Mediated KIF5A Deficiency Disrupts Anterograde Axonal Mitochondrial Movement(Academic Press Inc.) Wang, Qi; Tian, Jing; Chen, Hao; Du, Heng; Guo, Lan; Wang, Qi; Tian, Jing; Chen, Hao; Du, Heng; Guo, LanMitochondria are crucial organelles for neurophysiology and brain mitochondrial defects constitute a characteristic of Alzheimer's disease (AD). Impaired axonal mitochondrial traffic, especially the anterograde axonal mitochondrial transport is a pronouncing mitochondrial defect that underlies synaptic failure in AD-related conditions. However, the detailed molecular mechanisms of such axonal mitochondrial abnormality have not been fully understood. KIF5A is a key isoform of kinesin-1, which is a key molecular machinery in facilitating anterograde axonal mitochondrial transport. In this study, we have determined a downregulation of KIF5A in postmortem AD temporal lobes. Further experiments on amyloid beta (Aβ)-treated primary neuron culture and 5 × FAD mice suggest a close association of Aβ toxicity and KIF5A loss. Downregulation of KIF5A mimics Aβ-induced axonal mitochondrial transport deficits, indicating a potential role of KIF5A deficiency in AD-relevant axonal mitochondrial traffic abnormalities. Importantly, the restoration of KIF5A corrects Aβ-induced impairments in axonal mitochondrial transport, especially the anterograde traffic, with little or no impact on retrograde axonal mitochondrial motility. Our findings suggest a novel KIF5A-associated mechanism conferring Aβ toxicity to axonal mitochondrial deficits. Furthermore, the results implicate a potential therapeutic avenue by protecting KIF5A function for the treatment of AD. © 2019 Elsevier Inc.Item Brain Amyloidopathy in a Mouse Model of Alzheimer's Pathology(2020-05) Udhayakumar, Bhavatharini; Du, HengAlzheimer’s disease (AD) is a chronic neurodegenerative disorder, characterized by progressive cognitive decline. Presence of amyloid plaques and neurofibrillary tangles in the brain are hallmark AD pathology, which mediates synaptic injury and neuronal death, as well as neuroinflammation. Here we outline the various factors associated with brain amyloidosis in an AD mice models. We observed progressive Amyloid beta (A) production and deposition in the brain of the model mice. In addition, activation of microglia accompanies the development of amyloid plaques with age, which is associated with increased neuroinflammation in the mouse model.Item Cyclophilin D Deficiency Attenuates Mitochondrial F1Fo ATP Synthase Dysfunction Via OSCP In Alzheimer's Disease(Academic Press Inc Elsevier Science, 2018-09-26) Gauba, Esha; Chen, Hao; Guo, Lan; Du, Heng; Gauba, Esha; Chen, Hao; Guo, Lan; Du, HengMitochondrial dysfunction is pivotal in inducing synaptic injury and neuronal stress in Alzheimer's disease (AD). Mitochondrial F1Fo ATP synthase deregulation is a hallmark mitochondrial defect leading to oxidative phosphorylation (OXPHOS) failure in this neurological disorder. Oligomycin sensitivity conferring protein (OSCP) is a crucial F1Fo ATP synthase subunit. Decreased OSCP levels and OSCP interaction with amyloid beta (A beta) constitute key aspects of F1Fo ATP synthase pathology in AD-related conditions. However, the detailed mechanisms promoting such AD-related OSCP changes have not been fully resolved. Here, we have found increased physical interaction of OSCP with Cyclophilin D (CypD) in AD cases as well as in an AD animal model (5xFAD mice). Genetic depletion of CypD mitigates OSCP loss via ubiquitin-dependent OSCP degradation in 5xFAD mice. Moreover, the ablation of CypD also attenuates OSCP/A beta interaction in AD mice. The relieved OSCP changes by CypD depletion in 5xFAD mice are along with preserved F1Fo ATP synthase function, restored mitochondrial bioenergetics as well as improved mouse cognition. The simplest interpretation of our results is that CypD is a critical mediator that promotes OSCP deficits in AD-related conditions. Therefore, to block the deleterious impact of CypD on OSCP has the potential to be a promising therapeutic strategy to correct mitochondrial dysfunction for AD therapy.Item Cyclophilin D Deficiency Protects Against the Development of Mitochondrial ROS and Cellular Inflammation in Aorta(Academic Press Inc Elsevier Science, 2018-12-13) Liu, Xiaojing; Du, Heng; Chen, Dan; Yuan, Hai; Chen, Wenbin; Jia, Wenyu; Wang, Xiaolei; Li, Xia; Gao, Ling; Du, HengIntroduction: Inflammation and oxidative stress are closely correlated in the pathology of cardiovascular disease. Mitochondrial cyclophilin D (CypD), the important modulator for mPTP opening, is increasingly recognized as a key regulator of cellular ROS generation. Besides, its association with cell inflammation is also being discovered. However, the effects of CypD in modulating vascular inflammatory response is unknown. We sought to investigate whether CypD deficiency attenutes vascular inflammation under physical conditions. Methods and results: We adopted CypD KO mouse and their littermate controls to observe the effects of CypD deficiency on aortic mitochondrial functions and vascular inflammation. As we found in our study, we confirmed that under physical conditions, CypD deficiency enhanced mouse whole body metabolic status, increased aortic mitochondrial complex III activity and decreased mitochondrial ROS generation. Functionally, CypD deficiency also attenuated inflammatory molecules expression, including VCAM-1, IL-6 and TNF-alpha in mouse aorta. Conclusions: Our results review that mitochondrial CypD is involved in the regulation of inflammation in aorta and provide insights that blocking mitochondrial CypD enhances vascular resistance to inflammatory injuries.Item Deregulation of Mitochondrial F1FO-ATP Synthase via OSCP in Alzheimer's Disease(Nature Publishing Group) Beck, Simon J.; Guo, Lan; Phensy, Aarron; Tian, Jing; Wang, Lu; Tandon, Neha; Gauba, Esha; Lu, Lin; Pascual, J. M.; Kroener, Sven; Du, Heng; 0000-0003-1728-8111 (Kroener, S); Beck, Simon J.; Guo, Lan; Phensy, Aarron; Tian, Jing; Wang, Lu; Tandon, Neha; Gauba, Esha; Lu, Lin; Kroener, Sven; Du, HengF1FO-ATP synthase is critical for mitochondrial functions. The deregulation of this enzyme results in dampened mitochondrial oxidative phosphorylation (OXPHOS) and activated mitochondrial permeability transition (mPT), defects which accompany Alzheimerâ (tm) s disease (AD). However, the molecular mechanisms that connect F1FO-ATP synthase dysfunction and AD remain unclear. Here, we observe selective loss of the oligomycin sensitivity conferring protein (OSCP) subunit of the F1FO-ATP synthase and the physical interaction of OSCP with amyloid beta (Aβ) in the brains of AD individuals and in an AD mouse model. Changes in OSCP levels are more pronounced in neuronal mitochondria. OSCP loss and its interplay with Aβ disrupt F1FO-ATP synthase, leading to reduced ATP production, elevated oxidative stress and activated mPT. The restoration of OSCP ameliorates Aβ-mediated mouse and human neuronal mitochondrial impairments and the resultant synaptic injury. Therefore, mitochondrial F1FO-ATP synthase dysfunction associated with AD progression could potentially be prevented by OSCP stabilization.Item Ghrelin System Deficiency and Hippocampal Lesions in Alzheimer's Disease(2020-12-02) Tian, Jing; Du, HengAlzheimer’s Disease (AD) is a chronic neurodegenerative disorder that primarily affects the senior population and is characterized by insidious onset and progressive cognitive decline. AD is neuropathologically defined by Amyloid beta (Aβ) deposition, abnormal Tau phosphorylation, and neurodegeneration. In addition to these pathological features, synaptic injury in the hippocampus also constitutes an early and prominent characteristic of AD brains. The severity of hippocampal synaptic failure is closely associated with cognitive impairment in patients suffering from this neurodegenerative disorder. To date, the detailed molecular mechanisms conferring hippocampal synaptic vulnerability to Aβ toxicity in AD remain elusive and as a result, effective therapies targeting hippocampal synaptic deficits in AD are as of yet unavailable. Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor (GHSR), is a peptide found in both the gastrointestinal (GI) tract and in the brain. Previous studies on the ghrelin system predominantly focused on its functions in the GI tract, which include orexigenic, adipogenic, and somatotrophic properties. In recent years, the critical role of GHSR1α, the bioactive isoform of GHSR in maintaining hippocampal synaptic physiology has received increasing recognition. GHSR1α functions in modulating hippocampal synaptic activity largely through its regulation of dopamine receptor D1 (DRD1) by forming GHSR1α/DRD1 heterodimers. This dissertation addresses the critical question of whether the deregulation of GHSR is part of a key mechanism that causes hippocampal synaptic injury in AD-relevant pathological settings. Through observations of postmortem brain tissues and a mouse model mimicking AD-like amyloidosis (5×FAD mice), we unexpectedly found elevated levels of GHSR1α in the hippocampi of both AD patients and 5×FAD mice. However, further pathological and biochemical studies showed compromised GHSR1α function in Aβ-rich milieus, demonstrated by diminished GHSR1α response to its agonists. Furthermore, both AD patients and 5×FAD mice also exhibited reduced heterodimerization of GHSR1α with DRD1 in their hippocampi, despite preserved DRD1 expression levels. Consistent with the strong correlation between compromised GHSR1α function and Aβ levels, GHSR1α deregulation is, at least in part, a result of its physical binding with Aβ. This, along with AD-like hippocampal synaptic injuries in mice with genetic depletion of GHSR, adds credit to the hypothesis that GHSR1α dysfunction contributes to hippocampal synaptic lesions in AD, thereby indicating GHSR1α as a potential target for AD therapy. Despite this logical progression, our attempts to rescue hippocampal synaptic function by applying ghrelin or other GHSR agonists failed. In contrast, the co-activation of GHSR and DRD1 by a mixture of MK0677 (a specific GHSR agonist) and SKF81297 (a specific DRD1 agonist) restored GHSR1α response to agonist induced activation and protected against Aβ-mediated deficits in hippocampal synaptic function and mouse spatial learning and memory. In addition, the simultaneous application of a mixture of other GHSR1α and DRD1 agonists demonstrated a similar protective effect against Aβ-induced synaptic loss in primary hippocampal neuron cultures, further supporting the role of impaired GHSR1α regulation of DRD1 in the development of hippocampal synaptic injury in AD-related conditions. Collectively, our results suggest that GHSR1α deregulation contributes to hippocampal synaptic deficits and cognitive impairment in AD. The co-activation of GHSR1α and DRD1 holds promise in becoming a novel therapeutic avenue for the treatment of this devastating neurological disorder. Moreover, our study highlights the importance of GHSR1α’s regulation of DRD1 in hippocampal synaptic physiology.Item Mitochondria Dysfunction Induces Synapse Loss via Microglia Activation in AD Mice Model(2019-05) Rughwani, Tripta; Du, Heng; Guo, LanAlzheimer’s disease (AD) is a chronic cognitive impairment disorder associated with synapse loss. The synaptic sites are enriched in mitochondria to provide energy for synaptic transmission/ neurotransmission. During a pathological condition like AD, the synapse is actively engulfed by reactive microglia. However, involvement of microglia in synaptic pruning due to mitochondrial dysfunction is still unclear. Here we outline various parameters that define microglial reactivity in AD mouse models. Overexpression of Oligomycin Sensitivity Conferring Protein (OSCP), an important component of F1 Fo ATP synthase helps restore mitochondrial function and rescue synapse loss. In addition, microglia in early AD brains engulf synapse in a complement dependent manner. C1q, the initiating protein of classical complement pathway decreases on restoration of mitochondrial function with OSCP overexpression. Together, these findings suggest that mitochondrial dysfunction induce synapse loss via microglial activation in AD.Item Mitochondria-Dependent Local Caspase Activation and Mitofusin 2-Mediated Mitophagy in Neurodegeneration(2020-12-03) Chen, Hao; Du, HengMitochondria are critical regulators of neuronal physiology. They play a pivotal role in energy supply and Ca2+ buffering. Thus, mitochondria can sustain the synapse and neuronal function. In this regard, the mitochondria with an impaired capacity of bioenergetics or Ca2+ buffering will lead to synapse failure and neurodegeneration. Moreover, emerging evidence has shown that damaged mitochondria are also involved in local caspase activation, which coincides with spine pruning and neurodegeneration. However, the impacts of local caspase signaling on spine dynamics and neurodegeneration are still not clarified. To clarify them is critical for neurological disorders, in which the mitochondrial deficits are prominent and hard to be fixed. Additionally, as a pivotal mitochondrial enzyme – the F1Fo ATP synthase, dysfunction of it will lead to diseases with spinopathy. To this end, we inhibited the F1Fo ATP synthase by applying the sublethal oligomycin A to primary cultured neurons. Then, it induced the mitochondrial dysfunction and local caspase signaling. Following this, we blocked the caspase signaling through its inhibitor to determine whether it can rescue the spine elimination. In this case, we can dissect the caspase signaling out of mitochondrial energy supply and examine how much the caspase signaling attributes to spine pruning. Furthermore, we will find new ways to prevent the senescence of neurons through caspase inhibition. Moreover, mitochondrial quality control is of paramount importance for neuronal survival. Notably, mitophagy is a vital mechanism for maintenance of mitochondrial quality control. A previous study has shown that Mitofusin2 (Mfn2) plays a key role in mediating mitophagy in cardiomyocytes, which was demonstrated by decreased mitophagy in Mfn2 knockdown cardiomyocytes. In addition, lowered expression levels of Mfn2 have been repeatedly found in many neurodegenerative diseases like Alzheimer’s disease, which is characterized by the accumulation of damaged mitochondrial and mitophagosomes in neurons. In this regard, reduced Mfn2 expression may lead to compromised mitophagy and mitochondrial quality control. However, whether Mfn2 is indispensable for facilitating mitophagy has not been fully investigated. To this end, we knocked down Mfn2 in primary cultured neurons. Then, we examined the state of mitophagy. Intriguingly, we observed more mitophagosomes formation in Mfn2 knock-down neurons. It indicates the Mfn2 is not necessary for mitophagy induction. Such discrepancy may arise from the heterogeneity of different cell types. Also, it may arise from some alternative adaptor proteins, which can activate mitophagy. From previous reports, people pulled down the conjugated proteins from the outer mitochondrial membrane (OMM) of senescent and healthy neurons. After screening them by mass spectrum, they found that several OMM proteins may be the potential receptors for mitophagosome formation. Among them, Voltage-Dependent Anion Channel (VDAC) is the one most reported for mitophagy induction. Accordingly, we will further knockdown VDAC in Mfn2 knock-down neurons and examine the mitophagy states. In this case, we can determine whether VDAC can work as an Mfn2-independent alternative trigger for mitophagy in neurons. In all, both local caspases signaling and mitophagy play essential roles in neurodegeneration. Regulation of them may provide us new avenues for treating neurodegenerative diseases.Item Niclosamide Ethanolamine Improves Diabetes and Diabetic Kidney Disease in Mice(e-Century Publishing Corporation) Han, Pengxun; Shao, Mumin; Guo, Lan; Wang, Wenjing; Song, Gaofeng; Yu, Xuewen; Zhang, Chunlei; Ge, Na; Yi, Tiegang; Li, Shunmin; Du, Heng; Sun, Huili; Guo, Lan; Du, HengDiabetes and its renal complications are major medical challenges worldwide. There are no effective drugs currently available for treating diabetes and diabetic kidney disease (DKD), especially in type 1 diabetes (T1D). Evidence has suggested that niclosamide ethanolamine salt (NEN) could improve diabetic symptoms in mice of type 2 diabetes (T2D). However, its role in T1D and DKD has not been studied to date. Here we report that NEN could protect against diabetes in streptozotocin (STZ) induced T1D mice. It increased serum insulin levels, corrected the unbalanced ratio of alpha-cells to beta-cells, and induced islet morphologic changes under diabetic conditions. In addition, NEN could impede the progression of DKD in T1D. Specifically, it reduced urinary albumin levels, NAG, NGAL and TGF-beta 1 excretion, ameliorated renal hypertrophy, alleviated podocyte dysfunction, and suppressed the renal cortical activation of mTOR/4E-BP1 signaling pathway. Moreover, it is hepatoprotective and does not exhibit heart toxicity. Therefore, these findings open up a completely novel therapy for diabetes and DKD.Item Oligomycin Sensitivity Conferring Protein and Mitochondrial Deficits in the Aging Brain and Alzheimer's Disease(2019-01-10) Gauba, Esha; Du, HengBrain aging is the strongest risk factor for Alzheimer’s Disease (AD), in particular its sporadic form. However, the mechanism underlying the development of AD as a result of aging remains elusive. In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD, and are considered pivotal in inducing synaptic injury and neuronal stress. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increase in CypD expression, enhanced CypD/OSCP interaction and selective loss of OSCP are prominent brain mitochondrial changes in aging and AD mice. Furthermore, Aβ toxicity in AD-related pathophysiology augments CypD/OSCP interaction and exacerbates mitochondrial dysfunction. Moreover, the ablation of CypD relieves OSCP changes in the aging brain and 5xFAD mice along with preserved F1FO ATP synthase function, restored mitochondrial bioenergetics as well as improved mouse cognition (in AD mice). This suggests that CypD is a regulator of OSCP expression and promotes OSCP deficits, which causes mitochondrial dysfunction in brain aging and AD-related conditions. To further support our findings of CypD-mediated OSCP changes in the development of mitochondrial deficits in AD, we restored OSCP expression in AD mice by utilizing an original neuron-specific OSCP overexpressing mice. OSCP overexpressing AD mice exhibited significant protection from F1FO ATP synthase deregulation. Importantly, such protection accompanies preserved mitochondrial bioenergetics and blunted mitochondrial permeability transition pore (mPTP) formation as well as restored synaptic plasticity and transmission & improved cognition in AD mice. Thus, our findings collectively suggest that OSCP-associated mitochondrial deficits are common mechanisms in brain aging and AD and preserving OSCP expression has the potential to be a promising therapeutic strategy to correct mitochondrial dysfunction in brain aging and AD.Item Synaptosomal Mitochondrial Dysfunction In 5xFAD Mouse Model of Alzheimer's Disease(2018-06-01) Wang, Lu; Guo, Lan; Lu, Lin; Sun, Huili; Shao, Muming; Beck, Simon J.; Li, Lin; Ramachandran, Janani; Du, Yifeng; Du, Heng; 24824108100 (Du. H); Wang, Lu; Guo, Lan; Lu, Lin; Sun, Huili; Beck, Simon J.; Li, Lin; Ramachandran, Janani; Du, HengBrain mitochondrial dysfunction is hallmark pathology of Alzheimer’s disease (AD). Recently, the role of synaptosomal mitochondrial dysfunction in the development of synaptic injury in AD has received increasing attention. Synaptosomal mitochondria are a subgroup of neuronal mitochondria specifically locating at synapses. They play an essential role in fueling synaptic functions by providing energy on the site; and their defects may lead to synaptic failure, which is an early and pronounced pathology in AD. In our previous studies we have determined early synaptosomal mitochondrial dysfunction in an AD animal model (J20 line) overexpressing human Amyloid beta (Aβ), the key mediator of AD. In view of the limitations of J20 line mice in representing the full aspects of amyloidopathy in AD cases, we employed 5xFAD mice which are thought to be a desirable paradigm of amyloidopathy as seen in AD subjects. In addition, we have also examined the status of synaptosomal mitochondrial dynamics as well as Parkin-mediated mitophagy which have not been previously investigated in this mouse model. In comparison to nontransgenic (nonTg mice), 5xFAD mice demonstrated prominent synaptosomal mitochondrial dysfunction. Moreover, synaptosomal mitochondria from the AD mouse model displayed imbalanced mitochondrial dynamics towards fission along with activated Parkin and LC3BII recruitment correlating to spatial learning and memory impairments in 5xFAD mice in an age-dependent manner. These results suggest that synaptosomal mitochondrial deficits are primary pathology in Aβ-rich environments and further confirm the relevance of synaptosomal mitochondrial deficits to the development of AD.Item Transient Cerebral Ischemia Promotes Brain Mitochondrial Dysfunction and Exacerbates Cognitive Impairments in Young 5xFAD Mice(Public Library of Science, 2015-12-03) Lu, Lin; Guo, Lan; Gauba, Esha; Tian, Jing; Wang, Lu; Tandon, Neha; Shankar, Malini; Beck, Simon J.; Du, Yifeng; Du, Heng; Lu, Lin; Guo, Lan; Gauba, Esha; Tian, Jing; Wang, Lu; Tandon, Neha; Shankar, Malini; Beck, Simon J.; Du, HengAlzheimer's disease (AD) is heterogeneous and multifactorial neurological disorder; and the risk factors of AD still remain elusive. Recent studies have highlighted the role of vascular factors in promoting the progression of AD and have suggested that ischemic events increase the incidence of AD. However, the detailed mechanisms linking ischemic insult to the progression of AD is still largely undetermined. In this study, we have established a transient cerebral ischemia model on young 5xFAD mice and their non-transgenic (nonTg) littermates by the transient occlusion of bilateral common carotid arteries. We have found that transient cerebral ischemia significantly exacerbates brain mitochondrial dysfunction including mitochondrial respiration deficits, oxidative stress as well as suppressed levels of mitochondrial fusion proteins including optic atrophy 1 (OPA1) and mitofusin 2 (MFN2) in young 5xFAD mice resulting in aggravated spatial learning and memory. Intriguingly, transient cerebral ischemia did not induce elevation in the levels of cortical or mitochondrial Amyloid beta (Aß)1-40 or 1-42 levels in 5xFAD mice. In addition, the glucose- and oxygen-deprivation-induced apoptotic neuronal death in Aß-treated neurons was significantly mitigated by mitochondria-targeted antioxidant mitotempo which suppresses mitochondrial superoxide levels. Therefore, the simplest interpretation of our results is that young 5xFAD mice with pre-existing AD-like mitochondrial dysfunction are more susceptible to the effects of transient cerebral ischemia; and ischemic events may exacerbate dementia and worsen the outcome of AD patients by exacerbating mitochondrial dysfunction.;