Cardiovascular Dementia - A Different Perspective

The number of dementia patients has been growing in recent years and dementia represents a significant threat to aging people all over the world. Recent research has shown that the number of people affected by Alzheimer’s disease (AD) and dementia is growing at an epidemic pace. The rapidly increasing financial and personal costs will affect the world's economies, health care systems, and many families. Researchers are now exploring a possible connection among AD, vascular dementia (VD), diabetes mellitus (type 2, T2DM) and cardiovascular diseases (CD). This correlation may be due to a strong association of cardiovascular risk factors with AD and VD, suggesting that these diseases share some biologic pathways. Since heart failure is associated with an increased risk of AD and VD, keeping the heart healthy may prove to keep the brain healthy as well. The risk for dementia is especially high when diabetes mellitus is comorbid with severe systolic hypertension or heart disease. In addition, the degree of coronary artery disease (CAD) is independently associated with cardinal neuropathological lesions of AD. Thus, the contribution of T2DM and CD to AD and VD implies that cardiovascular therapies may prove useful in preventing AD and dementia

Characterization of the novel protein P9TLDR (temporal lobe down-regulated) with a brain-site-specific gene expression modality in Alzheimer’s disease brain

AbstractAlzheimer’s disease (AD) is an aging-related neurodegenerative disorder characterized by irreversible loss of higher cognitive functions. The disease is characterized by the presence of amyloid plaques and neurofibrillary tangles (NFT). In the current study we isolated from an intra-cerebral brain-site-specific (AD temporal lobe vs. AD occipital lobe) polymerase chain reaction (PCR)-select cDNA suppression subtractive hybridization (PCR-cDNA-SSH) expression analysis the novel gene P9TLDR, potentially a microtubule-associated protein involved in neuronal migration, with an altered expression pattern: down-regulated in the temporal lobe cortex of early stage AD brains. In an in vitro AD-related cell model, amyloid-β peptide (Aβ)-treated neurons, reduced P9TLDR expression correlated with increased tau protein phosphorylation. In conclusion, interference with the P9TLDR signalling pathways might be a therapeutic strategy for the treatment of AD

CRISPR-mediated upregulation of DR5 and downregulation of cFLIP synergistically sensitize HeLa cells to TRAIL-mediated apoptosis

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received attention as an anticancer therapy because it mediates apoptosis of several cancer cell types but not normal human cell types. In this study, we implemented genome editing techniques to upregulate DR5 and downregulate cFLIP in HeLa cells to stimulate TRAIL-induced apoptosis. We designed and validated sgRNAs to enrich the endogenous level of DRS by dead Cas9 (dCas9). Similarly, we designed two sgRNAs to disrupt the cFLIP gene by CRISPR/Cas9. We analyzed the effect of TRAIL on tumor cells by co-transfecting HeLa cells with the best combinations of sgRNAs regulating DR5 and cFLIP genes. TRAIL-induced apoptosis in HeLa cells was evaluated by the gamma H2AX foci formation assay to check for double-strand break and propidium iodide and Annexin V staining to quantify apoptotic cells. Viable cells were identified by CCK-8 assay, and cleaved-PARP level was evaluated by Western blot. This is the first study to demonstrate that genome editing techniques can be used as an effective combinatorial treatment strategy to induce apoptosis of cancer cells. In particular, enhancement of DR5 expression and inhibition of cFLIP expression by genome editing had a synergistic effect of inhibiting proliferation and inducing apoptosis in TRAIL-resistant HeLa cells. These results suggest that combinatorial treatment strategies mediated by the CRISPR/Cas9 system may be effective for design of other human TRAIL-resistant cell types. (C) 2019 Elsevier Inc. All rights reserved.This study was supported by a grant from the National Research Foundation of Korea (2017M3A9C6061361) and Medical Research Center (2017R1A5A2015395), funded by the National Research Foundation of Korea (NRF) of the Ministry of Science, ICT and Future Planning, Republic of Korea

Characterizing the signaling pathways of nerve growth factor in neuronal stem cells.

In recent years it has been noted that the adult brain has the 'self-repair capacity' to replace lost neurons in several regions of the central neural system (CNS), such as the olfactory bulb, hippocampus, adult human subependymal zone and the cortex. Neural stem cells (NSCs) within these neurogenic regions can proliferate and differentiate into neurons or glia, thus providing a tool of replacement cells to those lost during normal cell turnover and after brain injury. Neurogenesis involves the self-renewal and proliferation of NSCs, as well as its differentiation into neurons and glia which are tightly regulated by both intrinsic and extrinsic factors. Newborn neurons and glia then migrate to appropriate regions in the brain, and integrate into neuronal circuits (Heese et al., 2006)

Establishing a human adrenocortical carcinoma (ACC)-specific gene mutation signature

Adrenocortical carcinoma (ACC) is a rare and aggressive tumor whose molecular signaling pathways are not fully understood. Using an in-silico clinical data analysis approach we retrieved human gene mutation data from the highly reputed Cancer Genome Atlas (TCGA). ACC-specific gene mutations were correlated with proliferation marker FAM72 expression and Mutsig along with the algorithmic implementation of the 20/20 rule were used to validate their oncogenic potential. The newly identified oncogenic driver gene set (ZFPM1, LRIG1, CRIPAK, ZNF517, GARS and DGKZ), specifically and most repeatedly mutated in ACC, is involved in tumor suppression and cellular proliferation and thus could be useful for the prognosis and development of therapeutic approaches for the treatment of ACC.This study was supported by Hanyang University by providing a scholarship to C.S.R. and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A01057243 and 201681D1A1B03932599)

Gastrodia elata Blume (Tianma): Hope for Brain Aging and Dementia

Since aging-related diseases, including dementia, represent major public health threats to our society, physician-scientists must develop innovative, interdisciplinary strategies to open new avenues for development of alternative therapies. One such novel approach may lie in traditional Chinese medicine (TCM). Gastrodia elata Blume (G. elata, tianma) is a TCM frequently used for treatment of cerebrocardiovascular diseases (CCVDs). Recent studies of G. elata-based treatment modalities, which have investigated its pharmacologically relevant activity, potential efficacy, and safety, have employed G. elata in well-characterized, aging-related disease models, with a focus on models of aging-related dementia, such as Alzheimer’s disease (AD). Here, I examine results from previous studies of G. elata, as well as related herbal preparations and pure natural products, as prophylaxis and remedies for aging-related CCVDs and dementia. Concluding, data suggest that tianma treatment may be used as a promising complementary therapy for AD

Characterizing amyloid precursor protein (APP) signaling in neural stem cells.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by irreversible and progressive loss of money and deterioration of higher cognitive functions. The brain of an individual with AD exhibits extracellular senile plaques of aggregated amyloid-beta-peptide AB, intracellular neurofibrilary tangles (NFTs) that contain hyperphosphorylated tau protein (a microtubute associated protein) and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and the neocortex. Our observation that the NGF receptor TRKA os downregulated in AD brain led to our suggestion that an imbalance of neurotrophin receptor signalling may be involved in AD. AD appears to have a heterogeneous etiology and can be caused by mutations in the amyloid precursor protein (APP)gene on chromosome-21, the presenilin-1 (PS-1) gene on chromosome-14, and presenilin-2 (PS-2) gene on chromosome-1. Proteolytic processing of APP generates the amyloid-beta peptide (AB) and has been implicated in the pathogenesis of AD. APP fragments, including AB and APP's C-termial fragments (CTFs) or APP's intracellular domains (AICDs), have been reported to cause apoptosis. Mutations in the APP encoding gene and also in PS-1/2, which lead to early-onset AD, are associated with excess AB deposition in the brains of AD patient suggesting that the depositon of AB is a central disease-causing evant. However, the physiological function of APP and whether this function is related to the proteolytic processing of APP remains unclear. Moreover, the mechanism for the degeneration of nerve cells and synaptic connections that underlies the emergence of dementia, in particular in sporadic AD, is still unknown[1,2]RG 147/0

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease

One of the shared hallmarks of neurodegenerative diseases is the accumulation of misfolded proteins. Therefore, it is suspected that normal proteostasis is crucial for neuronal survival in the brain and that the malfunction of this mechanism may be the underlying cause of neurodegenerative diseases. The accumulation of amyloid plaques (APs) composed of amyloid-beta peptide (A beta) aggregates and neurofibrillary tangles (NFTs) composed of misfolded Tau proteins are the defining pathological markers of Alzheimer's disease (AD). The accumulation of these proteins indicates a faulty protein quality control in the AD brain. An impaired ubiquitin-proteasome system (UPS) could lead to negative consequences for protein regulation, including loss of function. Another pivotal mechanism for the prevention of misfolded protein accumulation is the utilization of molecular chaperones. Molecular chaperones, such as heat shock proteins (HSPs) and FK506-binding proteins (FKBPs), are highly involved in protein regulation to ensure proper folding and normal function. In this review, we elaborate on the molecular basis of AD pathophysiology using recent data, with a particular focus on the role of the UPS and molecular chaperones as the defensive mechanism against misfolded proteins that have prion-like properties. In addition, we propose a rational therapy approach based on this mechanism.This work was supported by the research fund of Hanyang University

Neurotrophins : more than Neurotrophic

The Nerve Growth Factor (NGF) is the prototypic member of the neurotrophin (NT) family, which plays an essential role in the development and functioning of the vertebrate nervous system. Although originally defined by their actions on neuronal survival and differentiation in the peripheral (PNS) and central nervous systems (CNS), accumulating data indicate the presence of extensive interactions between the NTs and the immune system. NTs are released normally during lymphocyte and leukocyte development by the bone marrow and the thymus and later by secondary lymph organs to maintain responsiveness of these circulating naïve and memory immune cells. Functional NT receptors have been detected on the cells of the immune system and increased levels of NGF protein are found during the acute phase of various diseases with a significant inflammatory component. Furthermore, in certain conditions such as allergic asthma, the released NTs exacerbate the severity of the inflammation and prolong the diseased state. However, in the CNS, if one can control homeostasis of the internal environment, then the natural response of the infiltrating immune cells to release these NTs can be used to intervene at key points in the disease progression. These wider functions are likely to be of concern in any attempted therapeutic use of NGF or related NTs.Accepted versio