Garrison Institute on Aging
Dr. Reddy's Highlights
A Keynote Presentation by P. Hemachandra Reddy, Ph.D. at Second International Conference on Neurology and Brain Disorders
Dr. P. Hemachandra Reddy, Executive Director and Chief Scientific Officer of Garrison Institute on Aging and a Professor Cell Biology and Biochemistry and Neuroscience/Pharmacology and Neurology Departments of School of Medicine was invited to give a keynote talk at the 2nd International Neurology and Brain Disorders (INBC), held at Rome, Italy June 4-6, 2018. Dr. Reddy presented a talk entitled ‘Abnormal Mitochondrial Dynamics and Defective Synapses: Protective Role of Reduced Dynamin-related protein 1 in Alzheimer’s Disease’ on June 5th. Dr. Reddy was honored with a certificate of recognition for his contributions to neurology and brain disorders at the conference.
Dr. Reddy explained how amyloid beta and phosphorylated tau damages mitochondria and synapses in neurons from patients with Alzheimer’s disease. He also presented compelling evidence that reduced levels of mitochondrial division protein ‘dynamin-related protein 1’ protects synapses and mitochondria in Alzheimer’s disease neurons. Currently, Dr. Reddy and his lab members are actively working on to develop drugs that can enhance synaptic sprouting and maintain mitochondrial ATP levels at synapses of Alzheimer’s disease neurons.
The INBC 2018 will bring together a collection of investigators who are at the forefront of their field and will provide opportunities for junior scientists and graduate students to interactively present their work and exchange ideas with established senior scientists. The Neurology and Brain Disorders conference explores the entire breadth of Neurology with earlier and contemporary work and provides a critical review of the present state of the subject. INBC 2018 provides an international forum to intensify the information exchange and is an excellent opportunity for Researchers and Scientists in the domain of Neurology from around the world and to promote/present innovative ideas that will influence and foster continued research. The speakers and delegates come from academia, private and government laboratories across the world.
MicroRNAs (miRNAs) are involved in growth, development, and occurrence and progression of many diseases. MiRNA mediated post-transcriptional regulation is poorly understood in vascular biology and pathology. The purpose of our study is to determine circulatory miRNAs as early detectable peripheral biomarkers in patients with ischemic stroke (IS). MiRNAs expression levels were measured in IS serum samples and healthy controls using Illumina deep sequencing analysis and identified differentially expressed miRNAs. Differentially expressed miRNAs were further validated using SYBR-green based quantitative real-time PCR assay (qRT-PCR) in postmortem IS brains, lymphoblastiod IS cell lines, OGD/R treated human and mouse neuroblastoma cells, and mouse models of hypoxia and ischemia (HI) induced stroke. A total of 4,656 moRNAs were differentially expressed in IS serum samples relative to healthy controls. Out of 4,656 miRNAs, 272 were found to be significantly deregulated in IS patients. Interestingly, we found several novel and previously unreported miRNAs in IS patients relative to healthy controls. Further analysis revealed that some candidate miRNAs and its target genes were involved in the revealed that some candidate miRNAs and its target genes were involved in the regulation of the stroke. To the best of our knowledge, this is the first study identified potential novel candidate miRNAs in IS serum samples from the residents of rural West Texas. MiRNAs identified in the present study could potentially be used as a biomarker and the development of novel therapeutic approaches for stroke. Further studies are necessary to better understand miRNAs-regulated stroke cellular changes.
Authors: Vijayan, Kumar, Yin, Zafer, Chanana, Cengiz, Reddy PH
The purpose of our study was to determine the toxic effects of hippocampal mutant APP and amyloid beta (AB) in human mutant APP (mAPP) cDNA transfected with primary mouse hippocampal neurons (HTT22). Hippocampal tissues are the best source of studying learning and memory functions in patients with Alzheimer's disease (AD) and healthy controls. However, investigating immortalized hippocampal neurons that express AD proteins provide an excellent opportunity for drug testing. Using quantitative RT-PCR, immunoblotting & immunofluorescence, and transmission electron microscopy, we assessed mRNA and protein levels of synaptic, sutophagy, mitophagy, mitochondrial dynamics, diogenesis, dendritic, dendritic protein MAP2, an assessed mitochondrial number and length in mAPP-HT22 cells that express Swedich/Indiana mutations. Mitochondrial function was assessed by measuring the levels of hydrogen peroxide, lipid perovidation, cytochrome c oxidase activity and mitochondrial ATP. Increased levels of mRNA and protein levels of mitochondrial fission genes, Drp1 and Fis1 and decreased levels fusion (Mfn1, Mfn2 and Opa1) biogenesis (PGC1a, NRF1, NRF2 & TFAM). autophagy (ATG5 & LC3BI, LC3BII), mitophagy (PINK1 & TERT, BCL2 & BNIPBL), synaptic (Synaptophysin & PSD95) and dendritic (MAP2) genes were found in mAPP-HT22 cells relative to WT-HT22 cells. Cell survival was significantly reduced mAPP-HT22 cells. GTPase-Dp1 enzymatic activity was increased in mAPP-HT22 cells. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in mAPP-HT22 cells. These findings suggest that hippocampal accumulation of mutant APP and AB is responsible for abnormal mitochondrial dynamics and defective biogenesis, reduced MAP2, autophagy, mitophagy and synaptic proteins & reduced dendritic spines and mitochondrial structural and functional changes in mutant APP hippocampal cels. These observations strongly suggest that accumulation of mAPP and AB causes mitochondrial, synaptic and autophagy/mitophagy abnormalities in hippocampal neurons, leading to neuronal dysfuntion.
Authors: Reddy PH, Yin, Manczah, Kumar, Jangampalli Adi, Vijayan, Reddy AP
A non-invasive and early-detectable peripheral biomarker is urgently needed for Alzheimer's disease (AD). The present study is a step forward to verify the biomarker Properties of human mocroRNA-455-3p (Hsa-miR-455-3p) in AD patients. Our previous findings on mild cognitive impaired subjects, AD patients and AD cells and mouse models unveiled the miR-455-3p as a potential peripheral biomarker for AD. In the current study, we verified the differential expression of miR-455-3p in post-mortem AD brains obtained from NIH NeuroBioBank, and fibroblasts and B-lympho-cytes from both familial and sporadic AD patients from Coriell Cell Repository of National Institutes on Aging. Total RNA was extracted from the fibroblasts, B-lympho-cytes and AD postmortem brains, and expression of miR-455-3p was measured by real-time reverse-transcriptase RT-PCR. Our real-time RT-PCR analysis showed a significant (P=0.0002) upregulation of miR-455-3p expression in AD postmortem brains compared to healthy control samples. Expression of miR-455-3p was also upregulated in the fibroblasts from AD patients, however a significant difference in miR-455-3p level was observed in the cell from sporadic AD patients (P=0.014) compared to healthy controls. Similarly, in B-lymphocytes, miR-455-3p level was also higher (P=0.044) especially in sporadic AD cases compared to controls. Receiver operating characteristic (ROC) curve analysis indicated the significant area under ROC curve (AUROC) value of miR-455-3p in AD postmortem brain (AUROC=0.792; P=0.001) and AD fibroblasts cells (AUROC=0.861;P=0.03), whereas in B-lymphocytes AUROC value of miR-455-3p was not significant. Further, in-silico analysis for miRNA targets predictions showed the binding capacity of miR-455-3p with several AD associated key genes such as APP, NGF, USP25, PDRG1, SMAD4, UBQLN1, SMAD2, TP73, VAMP2, HSPBAP1, and NRXN1. Hence, these observations further revealed that miR-455-3p is a potential biomarker for AD and its possible therapeutic target for AD.
Authors: Kumar, Reddy PH
The purpose of our study was to determine the toxic effects of hippocampal mutant APP and amyloid beta (AB) in 12 month old APP transgenic mice. Using rotarod and Morris water maze tests, immunoblotting and immunoflourescence, Golgi-cox staining and transmission electron microscopy, we assessed cognitive behavior, protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2 and quantified dendritic spines and mitochondrial number and length in 12 month-old APP mice that express Swedish mutation. Mitochondrial function was assessed by measuring the levels of hydrogen peroxide, lipid perocidation, cytochrome c oxidase activity and mitochondrial ATP. Morris water maze and rotarod test revealed that hippocampal learning and memory and motor learning and coordination were impaired in APP mice relative to wild-type (WT) mice. Increased levels of mitochondrial fission proteins, Drp1 and Fis1 and decreased levels of fusion (Mfn1, Mfn2 and Opa1) biogenesis (PGC1a, NRF1, NRF2 and TFAM), autophagy )ATG5 and LC3BI, LC3BII), mitophagy (Pink1 and TERT), synaptic (Synaptophysin and PSD95) and dendritic (MAP2) proteins were found in 12 month-old APP mice relative to age-matched non-transgenic WT mice. Golgi-cox staining analysis revealed that dendritic spines are significantly reduced. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in APP mice. These findings suggest that hippocampal accumulation of mutant APP and AB is responsible for abnormal mitochondrial dynamics and defective biogenesis, reduced MAP2, autophagy, mitophagy and synaptic proteins and reduced dendritic spines and hippocampal-based learning and memory impairments and mitochondrial structural and functional changes in 12 month-old APP mice.
Authors: Manczak, Kandimalla, Yin, Reddy PH
The purpose of our study was to determine the synergistic protective effects of mitochondria-targeted antioxidant SS31 and mitochondria division inhibitor 1 (Mdivi1) in Alzheimer's disease (AD). Using biochemical methods, we assessed mitochondrial function by measuring the levels of hydrogen peroxide, lipid peroxidation, cyto-chrome c oxidase activity, mitochondrial ATP, and GTPase Drp1 enzymatic activity in mutant ABPP cells. Using biochemical methods, we also measured cell survival and apoptotic cell death. Amyloid-B (AB) levels were measured using sandwich ELISA, and using real-time quantitative RT-PCR, we assessed mtDNA (mtDNA) copy number in relation to nuclear DNA (nDNA) in all groups of cells, We found significantly reduced levels of AB40 and AB42 in mutant ABPP cells treated with SS31, Mdici1, and SS31+Mdivi1, and the reduction of AB42 levels were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. The levels of mtDNA copy number and cell survival were significantly increased in SS31, Mdivi1, and SS31+Mdivi1 treated mutant ABPP cells; however, the increased levels of mtDNA copy number and cell survival were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. Mitochondrial dysfunctions is significantly reduced in SS31, Mdivi1, and SS31+Mdivi1 treated mutant ABPP cells; however, the reduction is much higher in cells treated with both SS31+Mdvi1. Similarly, GTPase Drp1 activity is reduced in all treatments, but reduced much higher in SS31+Mdivi1 treat cells. These observations strongly suggest that combined treatment of SS31+Mdivi1 is effective than individual treatments of SS31 and Mdivi1. Therefore, we propose that combined treatment of SS31+Mdivi1 is a better therapeutic strategy for AD. Ours is the first study to investigate combined treatment of mitochondria-targeted antioxidant SS31 and mitochondrial division inhibitor 1 in AD neurons.
Authors: Reddy PH, Manczak, Yin, Reddy AP
The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-B (AB)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used a diets and dietary supplements to treat human disesases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes and neurological disorders. Products derived from plants are known to have protective effects, including anti-infammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research of AM and curcumin has revealed that curcumin prevents AB in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailabitlity and urgent need for new formulations to increase its brain levels to treat patients with AD.
Authors; Reddy PH, Manczak, Yin, Grady, Mitchell, Tonk, Kuruva, Bhatti, Kandimalla, Vijayan, Kumar, Wang, Pradeepkiran, Ogunmokun, Thamarai, Quesada, Boles, Reddy AP
The purpose of our study was to understand the toxic effects of hippocampal phosphorylated tau in tau mice. Using rotarod and Morris water maze (MWM) tests, immunoblotting and immunoflourescence, Golgi-Cox staining and transmission electron microscopy, we assessed cognitive behavior, measured protein levels of mitochondrial dynamics, MAP2, total and phosphorylated tau, and quantified dendritic spines and mitochondrial number and length in 12 month-old tau mice with P301L mutation. Mitochondrial function was assessed by measuring the levels of H202, lipid perovidation, cytochrome oxidase activity and mitochondrial ATP. MWM and rotarod tests revealed that hoppocampal learning and memory and motor learning and coordination were impaired in tau mice relative to wild-type (WT) mice. Increased levels of mitochondrial fission proteins, Mfn1, Mfn2 and Pop1 were found in 12 month-old tau mice relative to age matched WT mice, indicating that the presence of abnormal mitochondrial dynamics in tau mice. Decreased levels of dendritic proteins were found in tau mice relative to WT mice. Mitochondrial functions was defective. Golgi-Cox staining analysis revealed that dendritic spines are significantly reduced. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in tau mice. These findings suggest that hippo-campal accumulation of phosphorylated tau is responsible for abnormal mitochondrial dynamics and reducing dendritic protein MAP2 and dendritic spines and hippocampal based learning and memory impairments, and mitochondrial structural and functional changes in tau mice. Based on these observations, we propose that reduced hippocampal phosphorylated tau is an important therapeutic strategy for AD and other tauopathies.
Authors: Kandimalla, Manczak, Yin, Wang, Reddy PH
In 1999, Texas Tech University Health Sciences Center leadership identified aging as a strategic priority for the 21st century. The Board of Regents approved the establishment of the Institute for Healthy Aging, which was renamed in February 2005 to the Garrison Institute on Aging (GIA), in honor of Mildred and Shirley L. Garrison.
The Garrison Institute on Aging (GIA) is the keystone of the TTUHSC initiative to help seniors successfully approach and extend the years of quality life. From investigating the causes of neurodegenerative diseases, to preparing health care professionals for the growing demands of geriatric care, the GIA is addressing health issues of aging population. The GIA is a collaborative initiative of the Health Sciences Center schools: Health Professions, Medicine, Nursing and Pharmacy.
The Garrison Institute on Aging is a unique organization whose mission is to promote healthy aging through cutting-edge research in Alzheimer's disease and other diseases of aging, and through innovative educational and community outreach programs that target students, clinicians, researchers, health care professionals and the public.
The vision of the institute is to become nationally and internationally recognized as a center of excellence for the creation and application of new knowledge about healthy aging through research, innovative interdisciplinary education and collaborative community outreach efforts.
Scientists at the Garrison Institute on Aging (GIA) are focusing on the connection between aging and disease. Our researchers are striving to develop treatments that will prevent or delay age-related disease. Our goal is to increase the health years of life - so that growing older no longer means growing ill.
Initiated in 2006 as the Cochran County Aging Study, Project FRONTIER (Facing Rural Obstacles to Healthcare Now Through Intervention, Education & Research) is an epidemiological study to explore the natural course of chronic disease development and its impact on longitudinal cognitive, physical, social and interpersonal functioning in a multi-ethnic adult sample from rural communities in West Texas.
The Healthy Lubbock Initiative seeks to make Lubbock and its surrounding communities a healthier place to live by supporting and encouraging people to improve nutrition, increase physical activity, and exercise regularly to promote wellness.
The goal of the Retired & Senior Volunteer Program (RSVP) is to utilize the interests, skills and abilities of this growing population of older adults by providing stimulating opportunities for personal development through placement in satisfying and rewarding positions in volunteer service areas.
TTUHSC Researcher Receives National Institute of Health Grant
The National Institute of Health (NIH) awarded P. Hemachandra Reddy, Ph.D., the executive director and chief scientific officer of the Texas Tech University Health Sciences Centers Garrison Institute on Aging (GIA), a $1.9 million, five-year R01 grant from the Neurological Disorders and Stroke Institute of the National Institutes of Health.
PI: P. Hemachandra Reddy, PhD.
"Mitochondrial Fragmentation and Neurodegeneration in Huntington's Disease."
PI: P. Hemachandra Reddy, PhD.; Co-PI: Arubala Reddy, PhD.
"Saga(Sex and Gender) Grant from Alzheimer's Association."
Click HERE to view all ongoing Research Grants and Outreach Support at the GIA.
In 2017, the Garrison Institute on Aging was a significant contributor to this important
body of knowledge. Under the leadership of Dr. Hemachandra Reddy, our researchers
continue to conduct novel research in these areas with the hope that one day their
findings will translate into strategies or treatments to prevent, delay or slow age-related
Tedd L. Mitchell, MD
President Texas Tech University Health Sciences Center
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