Browsing by Author "Tian, Jing"
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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 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 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.;