Low Serum Phosphorus Correlates with Cerebral Aβ Deposition in Cognitively Impaired Subjects: Results from the KBASE Study

Park, Jong-Chan,Han, Sun-Ho,Byun, Min S.,Yi, Dahyun,Lee, Jun Ho,Park, Kyua,Lee, Dong Young,Mook-Jung, Inhee Frontiers Media S.A. 2017 FRONTIERS IN AGING NEUROSCIENCE Vol.9 No.-

<P>Alzheimer's disease (AD), characterized by progressive cognitive decline, is the most prevalent neurodegenerative disease in the elderly. Cerebral β-amyloid (Aβ) deposition is the major pathological hallmark of AD. Recent studies also have shown that the serum level of phosphorus correlates to the risk of incident dementia. To date, the linkage between cerebral Aβ deposition and the serum phosphorus level remains unknown. In this study, we analyzed the levels of serum phosphorus in 109 mild cognitive impairment (MCI) and 73 AD dementia (ADD) subjects. All subjects underwent Pittsburgh compound B positron emission tomography (PiB-PET) imaging to measure cerebral Aβ deposition. The results with Aβ deposition was compared with the serum levels of phosphorus. The subjects with cerebral Aβ deposition showed lower levels of serum phosphorus than those without Aβ deposition. Furthermore, multiple regression analyses showed that a low level of serum phosphorus correlated with cerebral Aβ deposition, even when age, sex, apolipoprotein E ε4 genotype, and MMSE z-score were controlled for. Serum levels of other ions, including calcium, iron, zinc, and copper, showed no such correlation. In conclusion, our results suggest that the serum level of phosphorus may be used as an easily accessible blood biomarker for cerebral Aβ deposition in a cognitively impaired population.</P>

Perspective Insights into Disease Progression, Diagnostics, and Therapeutic Approaches in Alzheimer's Disease: A Judicious Update

Jan, Arif Tasleem,Azam, Mudsser,Rahman, Safikur,Almigeiti, Angham M. S.,Choi, Duk Hwan,Lee, Eun Ju,Haq, Qazi Mohd Rizwanul,Choi, Inho Frontiers Media S.A. 2017 FRONTIERS IN AGING NEUROSCIENCE Vol.9 No.-

<P>Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive accumulation of β-amyloid fibrils and abnormal tau proteins in and outside of neurons. Representing a common form of dementia, aggravation of AD with age increases the morbidity rate among the elderly. Although, mutations in the ApoE4 act as potent risk factors for sporadic AD, familial AD arises through malfunctioning of APP, PSEN-1, and−2 genes. AD progresses through accumulation of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) in brain, which interfere with neuronal communication. Cellular stress that arises through mitochondrial dysfunction, endoplasmic reticulum malfunction, and autophagy contributes significantly to the pathogenesis of AD. With high accuracy in disease diagnostics, Aβ deposition and phosphorylated tau (p-tau) are useful core biomarkers in the cerebrospinal fluid (CSF) of AD patients. Although five drugs are approved for treatment in AD, their failures in achieving complete disease cure has shifted studies toward a series of molecules capable of acting against Aβ and p-tau. Failure of biologics or compounds to cross the blood-brain barrier (BBB) in most cases advocates development of an efficient drug delivery system. Though liposomes and polymeric nanoparticles are widely adopted for drug delivery modules, their use in delivering drugs across the BBB has been overtaken by exosomes, owing to their promising results in reducing disease progression.</P>

Amyloid β1-42 (Aβ1-42) Induces the CDK2-Mediated Phosphorylation of Tau through the Activation of the mTORC1 Signaling Pathway While Promoting Neuronal Cell Death

Lee, Ki Hoon,Lee, Sei-Jung,Lee, Hyun Jik,Choi, Gee Euhn,Jung, Young Hyun,Kim, Dah Ihm,Gabr, Amr Ahmed,Ryu, Jung Min,Han, Ho Jae Frontiers Media S.A. 2017 Frontiers in molecular neuroscience Vol.10 No.-

<P>Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment and memory loss. Amyloid β1-42 (Aβ) and hyper-phosphorylation of microtubule-associated protein tau have been considered as major histological features in AD. However, the mechanism of how Aβ induces the hyper-phosphorylation of tau remains to be clarified. In the present study, we investigated the underlying cellular mechanisms of Aβ with regard to the cell cycle regulatory protein-mediated phosphorylation of tau in promoting neuronal cell death. The oligomer Aβ (5 μM) significantly increased the level of caspase 3 cleavage and has the ability to induce cytotoxicity in human neuroblastoma SK-N-MC cells. Aβ induced the degree of extracellular calcium influx via the L-type channel to facilitate the production of reactive oxygen species (ROS). Aβ signaling through ROS production is uniquely mediated by the activation of PI3K/Akt, which is in turn required for mammalian target of rapamycin complex 1 (mTORC1) phosphorylation. mTORC1 activated by Aβ further increased the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), a binding protein (4E-BP1) and p70S6K1 to stimulate the HIF1α synthesis responsible for the induction of cyclinD<SUB>1</SUB>/cyclin-dependent kinase 4 (CDK4) and cyclinE/CDK2, whereas it significantly attenuated the activation of autophagy. Aβ distinctively induced the CDK2-mediated phosphorylation of tau, which is responsible for microtubule destabilization in promoting neuronal apoptosis. In mouse hippocampal primary neurons, the apoptotic cell death induced by Aβ is highly susceptible to the mTORC1 signaling pathway. These results demonstrate that Aβ efficiently stimulates the mTORC1 signaling pathway to facilitate HIF1α synthesis and autophagy inhibition to promote the expression of cell cycle regulatory proteins, during which CDK2 uniquely stimulates tau phosphorylation for microtubule destabilization-mediated neuronal apoptosis.</P>

Early-Life Cognitive Activity Is Related to Reduced Neurodegeneration in Alzheimer Signature Regions in Late Life

Ko, Kang,Byun, Min Soo,Yi, Dahyun,Lee, Jun Ho,Kim, Chan Hyung,Lee, Dong Young Frontiers Media S.A. 2018 FRONTIERS IN AGING NEUROSCIENCE Vol.10 No.-

<P><B>Background:</B> Although increased cognitive activity (CA), both current and past, is known to be associated with a decreased occurrence of Alzheimer’s disease (AD) dementia in older adults, the exact neural mechanisms underlying the association between CA during different stages of life and human dementia remain unclear. Therefore, we investigated whether CA during different life stages is associated with cerebral amyloid-beta (Aβ) pathology and AD-related neurodegeneration in non-demented older adults.</P><P><B>Methods:</B> Cross-sectional analyses of data collected between April 2014 and March 2016 from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort. In total, 321 community-dwelling, non-demented older adults were involved in this study. Cerebral Aβ deposition and Aβ positivity were measured using <SUP>11</SUP>C-Pittsburgh compound B (PiB)-positron emission tomography (PET). AD-signature region cerebral glucose metabolism (AD-CMglu) and AD-signature region neurodegeneration (AD-ND) positivity were measured using <SUP>18</SUP>F-fluorodeoxyglucose (FDG)-PET. In addition, CA in early, mid, and late life was systematically evaluated using a structured questionnaire.</P><P><B>Results:</B> Of the 321 participants, 254 were cognitively normal (CN) and 67 had mild cognitive impairment (MCI). The mean age of participants was 69.6 years old [standard deviation (SD) = 8.0]. Higher early-life CA (CA<SUB>early</SUB>) was associated with significantly increased AD-CMglu (<I>B</I> = 0.035, SE = 0.013, <I>P</I> = 0.009) and a decreasing trend of AD-ND positivity (OR = 0.65, 95% CI 0.43–0.98, <I>P</I> = 0.04) but was not associated with Aβ deposition or positivity. We observed no association between midlife CA (CA<SUB>mid</SUB>) and any AD-related brain changes. Late-life CA (CA<SUB>late</SUB>) showed an association with both global Aβ deposition and AD-CMglu, although it was not statistically significant. Sensitivity analyses controlling for current depression or conducted only for CN individuals revealed similar results.</P><P><B>Conclusion:</B> Our results suggest that CA in early life may be protective against late-life AD-related neurodegeneration, independently of cerebral Aβ pathology.</P>

Importance of GPCR-Mediated Microglial Activation in Alzheimer’s Disease

Haque, Md. Ezazul,Kim, In-Su,Jakaria, Md.,Akther, Mahbuba,Choi, Dong-Kug Frontiers Media S.A. 2018 Frontiers in cellular neuroscience Vol.12 No.-

<P>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with impairment of cognition, memory deficits and behavioral abnormalities. Accumulation of amyloid beta (Aβ) is a characteristic hallmark of AD. Microglia express several GPCRs, which, upon activation by modulators, mediate microglial activation and polarization phenotype. This GPCR-mediated microglial activation has both protective and detrimental effects. Microglial GPCRs are involved in amyloid precursor protein (APP) cleavage and Aβ generation. In addition, microglial GPCRs are featured in the regulation of Aβ degradation and clearance through microglial phagocytosis and chemotaxis. Moreover, in response to Aβ binding on microglial Aβ receptors, they can trigger multiple inflammatory pathways. However, there is still a lack of insight into the mechanistic link between GPCR-mediated microglial activation and its pathological consequences in AD. Currently, the available drugs for the treatment of AD are mostly symptomatic and dominated by acetylcholinesterase inhibitors (AchEI). The selection of a specific microglial GPCR that is highly expressed in the AD brain and capable of modulating AD progression through Aβ generation, degradation and clearance will be a potential source of therapeutic intervention. Here, we have highlighted the expression and distribution of various GPCRs connected to microglial activation in the AD brain and their potential to serve as therapeutic targets of AD.</P>

Comparison of Administration Routes on the Protective Effects of Bee Venom Phospholipase A2 in a Mouse Model of Parkinson’s Disease

Baek, Hyunjung,Jang, Hyun Il,Jeon, Hat Nim,Bae, Hyunsu Frontiers Media S.A. 2018 FRONTIERS IN AGING NEUROSCIENCE Vol.10 No.-

<P>Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. Progressive loss of dopaminergic neurons in the substantia nigra (SN) and their synaptic terminal connections in the striatum are main characterizations of PD. Although many efforts have been made to develop therapeutics, no treatment has been proven effective. We previously demonstrated that bvPLA2 can protect dopaminergic neurons by modulating neuroinflammatory responses in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD. The cellular basis for the neuroprotective response of bvPLA2 was the induction of CD4<SUP>+</SUP>CD25<SUP>+</SUP> regulatory T cells (Tregs), a population known to suppress immune activation and maintain homeostasis and tolerance to self-antigen. The aim of the present study was to investigate the effects of different routes of bvPLA2 administration in a PD mouse model. Neurobehavioral assessment revealed progressive deterioration in locomotor functions of the MPTP group compared with the control group. However, such functions were improved following subcutaneous (s.c.) bvPLA2 administration. The results showed that the s.c. route of bvPLA2 administration contributed to the induction of Treg cells and the reduction of Th1 and Th17 populations, demonstrating that the neuroprotective effects were associated with reduced tyrosine hydroxylase (TH)-positive dopaminergic neurons and microglia. These results suggested that the s.c. bvPLA2 injection could be beneficial for treating aspects of PD.</P>

PDI Knockdown Inhibits Seizure Activity in Acute Seizure and Chronic Epilepsy Rat Models via <i>S</i> -Nitrosylation-Independent Thiolation on NMDA Receptor

Jeon, A. Ran,Kim, Ji-Eun Frontiers Media S.A. 2018 Frontiers in cellular neuroscience Vol.12 No.-

<P>Redox modulation and <I>S</I>-nitrosylation of cysteine residues are the post-translational modifications of <I>N</I>-methyl-D-aspartate receptor (NMDAR) to regulate its functionality. Recently, we have reported that protein disulfide isomerase (PDI) reduces disulfide bond (S-S) to free thiol (-SH) on NMDAR. Since PDI is a modulator of <I>S</I>-nitrosylation on various proteins, it is noteworthy whether PDI affects <I>S</I>-nitrosylation of NMDAR in acute seizure and chronic epilepsy models. In the present study, we found that acute seizures in response to pilocarpine and spontaneous seizures in chronic epilepsy rats led to the reduction in <I>S</I>-nitrosylated thiol (SNO-thiol)-to-total thiol ratio on NMDAR, while they elevated nitric oxide (NO) level and <I>S</I>-nitrosylation on NMDAR. <I>N</I>-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor) did not affect seizure activities in both models, although it decreased SNO-thiol levels on NMDAR. However, PDI knockdown effectively inhibited pilocarpine-induced acute seizures and spontaneous seizures in chronic epilepsy rats, accompanied by increasing the SNO-thiol-to-total thiol ratio on NMDAR due to diminishing the amounts of total thiols on GluN1 and GluN2A. Therefore, these findings indicate that PDI may not be a NO donor or a denitrosylase for NMDAR, and that PDI knockdown may inhibit seizure activity by the <I>S</I>-nitrosylation-independent thiolation on NMDAR.</P>

Movement-Related Sensorimotor High-Gamma Activity Mainly Represents Somatosensory Feedback

Ryun, Seokyun,Kim, June S.,Jeon, Eunjeong,Chung, Chun K. Frontiers Media S.A. 2017 Frontiers in neuroscience Vol.11 No.-

<P>Somatosensation plays pivotal roles in the everyday motor control of humans. During active movement, there exists a prominent high-gamma (HG >50 Hz) power increase in the primary somatosensory cortex (S1), and this provides an important feature in relation to the decoding of movement in a brain-machine interface (BMI). However, one concern of BMI researchers is the inflation of the decoding performance due to the activation of somatosensory feedback, which is not elicited in patients who have lost their sensorimotor function. In fact, it is unclear as to how much the HG component activated in S1 contributes to the overall sensorimotor HG power during voluntary movement. With regard to other functional roles of HG in S1, recent findings have reported that these HG power levels increase before the onset of actual movement, which implies neural activation for top-down movement preparation or sensorimotor interaction, i.e., an efference copy. These results are promising for BMI applications but remain inconclusive. Here, we found using electrocorticography (ECoG) from eight patients that HG activation in S1 is stronger and more informative than it is in the primary motor cortex (M1) regardless of the type of movement. We also demonstrate by means of electromyography (EMG) that the onset timing of the HG power in S1 is later (49 ms) than that of the actual movement. Interestingly, we show that the HG power fluctuations in S1 are closely related to subtle muscle contractions, even during the pre-movement period. These results suggest the following: (1) movement-related HG activity in S1 strongly affects the overall sensorimotor HG power, and (2) HG activity in S1 during voluntary movement mainly represents cortical neural processing for somatosensory feedback.</P>

Dose-Dependent Neuroprotective Effect of Standardized Bee Venom Phospholipase A ₂ Against MPTP-Induced Parkinson’s Disease in Mice

Kim, Kyung Hwa,Lee, Seung Young,Shin, Jaekwon,Hwang, Jae-Taeg,Jeon, Hat Nim,Bae, Hyunsu Frontiers Media S.A. 2019 FRONTIERS IN AGING NEUROSCIENCE Vol.11 No.-

<P>Parkinson’s disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons within the substantia nigra (SN). While the precise etiology of dopaminergic neuronal demise is elusive, multiple lines of evidence indicate that neuroinflammation is involved in the pathogenesis of PD. We have previously demonstrated that subcutaneous administration of bee venom (BV) phospholipase A<SUB>2</SUB> (bvPLA<SUB>2</SUB>) suppresses dopaminergic neuronal cell death in a PD mouse model. In the present study, we established standardized methods for producing bvPLA<SUB>2</SUB> agent isolated from crude BV at good manufacturing practice (GMP) facility. The therapeutic efficacy of purified bvPLA2 agent was examined in MPTP-induced PD mice. Importantly, administration of purified bvPLA<SUB>2</SUB> in a dose-dependent manner reversed motor deficits in PD mice as well as inhibited loss of dopaminergic neurons within the SN of PD mice. The concentration-dependent action of standardized bvPLA<SUB>2</SUB> appeared to be related to the induction of CD4<SUP>+</SUP>CD25<SUP>+</SUP>Foxp3<SUP>+</SUP> regulatory T cells (Tregs), which, in part, inhibits T helper 1 (Th1) and Th17 polarization and suppresses microglial activation in PD mice. Taken together, these results suggest that standardized bvPLA<SUB>2</SUB> purified from BV shows a neuroprotective effect against PD and thus has a potential target for treatment of PD.</P>

Adiponectin Regulates the Polarization and Function of Microglia via PPAR-γ Signaling Under Amyloid β Toxicity

Song, Juhyun,Choi, Seong-Min,Kim, Byeong C. Frontiers Media S.A. 2017 Frontiers in cellular neuroscience Vol.11 No.-

<P>Alzheimer’s disease (AD), characterized by the abnormal accumulation of amyloid beta (Aβ), is gradually increasing globally. Given that AD is considered a neuroinflammatory disease, recent studies have focused on the cellular mechanisms in brain inflammatory conditions that underlie AD neuropathology. Microglia are macrophage cells in the central nervous system (CNS) that are activated in response to Aβ condition. The function of microglia contributes to the neuroinflammation in AD brain, suggesting that microglia regulate the production of inflammatory mediators and contribute to the regeneration of damaged tissues. Adiponectin, an adipokine derived from adipose tissue, has been known to regulate inflammation and control macrophages during oxidative stress conditions. In present study, we investigated whether adiponectin influences the polarization and function of microglia under Aβ toxicity by examining alterations of BV2 microglia function and polarization by Acrp30 (a globular form of adiponectin) treatment using reverse transcription PCR, western blotting and immunofluorescence staining. Acrp30 promoted the induction of the M2 phenotype, and regulated the inflammatory responses through peroxisome proliferator-activated receptor (PPAR)-γ signaling under Aβ toxicity. In addition, Acrp30 boosted the capacity of Aβ scavenging in microglia. Taken together, we suggest that adiponectin may control the function of microglia by promoting anti-inflammatory responses through PPAR- γ signaling. Hence, we conclude that adiponectin may act as a critical controller of microglia function in the AD brain.</P>