Arubala P. Reddy, Ph.D.

Research Focus

My current research focuses on better understanding underlying mechanism of AD using postmortem brains from humans with Alzheimer's disease (AD) and from AD cell and mouse models. My research centers on the hypothesis that molecule-targeting serotonin (5HT) has a significant role in forebrain neuromodulation and increasing synaptic density in neurons and that in a healthy state, 5HT is transmitted throughout the brain, ultimately resulting in neuroprotection against AD pathology. The isodendritic core (IDC) of the brain stem (midbrain, pons) – defined by the substantia nigra (dopamine-enriched neurons), raphe (serotonin-enriched neurons), and locus ceruleous (norepinephrine-enriched neurons) – has synchronized a modulating cascade of AD that controls energy homeostasis in the basal forebrain by targeting cholinergic neurons of the basalis of meynert. To investigate our hypothesis, we need to better understand global mRNA expression analysis in dopaminergic, serotonergic, and noradrenergic neurons. In the future, a better understanding of AD neurons will help us develop new drug targets for AD help us to understand gender dimorphism in IDC, and define new biomarkers. I bring over 15 years of research experience investigating mechanisms of serotonin in the human central nervous system (CNS) and the impact of hormones and antidepressants on the serotonin cascade. I have extensively studied nonhuman primate models of the, and cell and mouse models of AD to better understand the role of serotonin in synaptic plasticity, neuroplasticity, CNS neurotransmission, neurogenesis, and neuronal proliferation, in the following areas of the brain: midbrain dorsal raphe nucleus (DRN), hypothalamus, hippocampus, pons, cerebellum, and frontal cortex. My research has resulted in identifying the role of serotonin transmission in the brain and the role of serotonin activation on energy metabolisms of the cell – actions that lead to the cascade of 5HT in higher-order functioning. My research includes findings that neurosteroids and antidepressants affect serotonin neurons and define a protective role for serotonin in AD pathology. As a molecular biologist, I have extensively used genomics as a tool for my research. In 2000, I began working on a global gene expression analysis, and since then, I have participated in multiple research projects, most of which resulted in published papers. My most recent global gene expression analysis of midbrain serotonin neurons from healthy postmortem human brains has shown gender disparity in the role of serotonin in altering energy metabolism, including regulating many key physiological pathways. Based on these findings, I am investigating whether this gender disparity also exists in the DRN of persons with AD, traumatic brain injury (TBI), and posttraumatic stress syndrome. To better understand the protective effects of the serotonin network, I am also determining the effects of neurosteroids and antidepressant treatments on AD cells in APP and tau mice. Other SSRIs besides serotonin, such as citalopram, have been found to target molecules involved in TBI and major depression. This finding suggests the hypothesis that serotonin may be useful in delivering neuroprotective drugs in persons with AD, TBI, and major depression. I will be working on investigating this hypothesis in the proposed research. Overall, I significantly contributed to serotonin and AD, published over 55 peer-reviewed articles, chapters and reviews – these can be viewed on the following website: https://www.ncbi.nlm.nih.gov/pubmed/?term=reddy+ap

Selected Publications

1: Bhatti GK, Reddy AP, Reddy PH, Bhatti JS. Lifestyle Modifications and Nutritional Interventions in Aging-Associated Cognitive Decline and Alzheimer'sDisease. Front Aging Neurosci. 2020 Jan 10;11:369. doi:10.3389/fnagi.2019.00369. PMID: 31998117; PMCID: PMC6966236.

2: Reddy AP, Ravichandran J, Carkaci-Salli N. Neural regeneration therapies for Alzheimer's and Parkinson's disease-related disorders. Biochim Biophys Acta MolBasis Dis. 2020 Apr 1;1866(4):165506. doi: 10.1016/j.bbadis.2019.06.020. Epub 2019 Jul 2. PMID: 31276770.

3: Kumar S, Reddy AP, Yin X, Reddy PH. Novel MicroRNA-455-3p and its protective effects against abnormal APP processing and amyloid beta toxicity in Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2428-2440. doi: 10.1016/j.bbadis.2019.06.006. Epub 2019 Jun 8. PMID: 31181293; PMCID:PMC6688505.

4: Makena MR, Ranjan A, Thirumala V, Reddy AP. Cancer stem cells: Road to therapeutic resistance and strategies to overcome resistance. Biochim Biophys Acta Mol Basis Dis. 2020 Apr 1;1866(4):165339. doi:10.1016/j.bbadis.2018.11.015. Epub 2018 Nov 24. PMID: 30481586.

5: Reddy PH, Yin X, Manczak M, Kumar S, Pradeepkiran JA, Vijayan M, Reddy AP.Mutant APP and amyloid beta-induced defective autophagy, mitophagy,mitochondrial structural and functional changes and synaptic damage inhippocampal neurons from Alzheimer's disease. Hum Mol Genet. 2018 Jul15;27(14):2502-2516. doi: 10.1093/hmg/ddy154. PMID: 29701781; PMCID: PMC6031001.

6: Reddy PH, Manczak M, Yin X, Grady MC, Mitchell A, Tonk S, Kuruva CS, Bhatti JS, Kandimalla R, Vijayan M, Kumar S, Wang R, Pradeepkiran JA, Ogunmokun G,Thamarai K, Quesada K, Boles A, Reddy AP. Protective Effects of Indian SpiceCurcumin Against Amyloid-β in Alzheimer's Disease. J Alzheimers Dis.2018;61(3):843-866. doi: 10.3233/JAD-170512. PMID: 29332042; PMCID: PMC5796761.

7: Bethea CL, Mueller K, Reddy AP, Kohama SG, Urbanski HF. Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques. PLoSOne. 2017 Jun 19;12(6):e0178788. doi: 10.1371/journal.pone.0178788. PMID: 28628658; PMCID: PMC5476244.

8: Reddy AP, Reddy PH. Mitochondria-Targeted Molecules as Potential Drugs toTreat Patients With Alzheimer's Disease. Prog Mol Biol Transl Sci.2017;146:173-201. doi: 10.1016/bs.pmbts.2016.12.010. Epub 2017 Feb 11. PMID:28253985. 

9: Reddy PH, Williams J, Smith F, Bhatti JS, Kumar S, Vijayan M, Kandimalla R,Kuruva CS, Wang R, Manczak M, Yin X, Reddy AP. MicroRNAs, Aging, Cellular Senescence, and Alzheimer's Disease. Prog Mol Biol Transl Sci. 2017;146:127-171.doi: 10.1016/bs.pmbts.2016.12.009. Epub 2017 Feb 2. PMID: 28253983.

10: Bethea CL, Reddy AP, Christian FL. How Studies of the Serotonin System in Macaque Models of Menopause Relate to Alzheimer's Disease1. J Alzheimers Dis.2017;57(4):1001-1015. doi: 10.3233/JAD-160601. PMID: 27662311; PMCID:PMC5575917. 

11: Reddy PH, Tonk S, Kumar S, Vijayan M, Kandimalla R, Kuruva CS, Reddy AP. Acritical evaluation of neuroprotective and neurodegenerative MicroRNAs inAlzheimer's disease. Biochem Biophys Res Commun. 2017 Feb 19;483(4):1156-1165. doi: 10.1016/j.bbrc.2016.08.067. Epub 2016 Aug 12. PMID: 27524239; PMCID:PMC5343756.

12: Bethea CL, Kohama SG, Reddy AP, Urbanski HF. Ovarian steroids regulate gene expression in the dorsal raphe of old female macaques. Neurobiol Aging. 2016 Jan;37:179-191. doi: 10.1016/j.neurobiolaging.2015.10.004. Epub 2015 Oct 19.PMID: 26686671; PMCID: PMC4699313.

13: Bethea CL, Phu K, Kim A, Reddy AP. Androgen metabolites impact CSF amines and axonal serotonin via MAO-A and -B in male macaques. Neuroscience. 2015 Aug 20;301:576-89. doi: 10.1016/j.neuroscience.2015.06.020. Epub 2015 Jun 16. PMID:26086546; PMCID: PMC4520442.

14: Varlamov O, Kievit P, Phu K, Reddy AP, Roberts CT Jr, Bethea CL. Preliminary Examination of Olanzapine and Diet Interactions On Metabolism in a Female Macaque. J Endocrinol Diabetes. 2014;1(2):9. doi: 10.15226/2374-6890/1/2/00112.PMID: 25621305; PMCID: PMC4301435.

15: Bethea CL, Reddy AP. Ovarian steroids regulate gene expression related to DNA repair and neurodegenerative diseases in serotonin neurons of macaques. Mol Psychiatry. 2015 Dec;20(12):1565-78. doi: 10.1038/mp.2014.178. Epub 2015 Jan 20.PMID: 25600110; PMCID: PMC4508249.

16: Bethea CL, Reddy AP, Flowers M, Shapiro RA, Colman RJ, Abbott DH, Levine JE.High fat diet decreases beneficial effects of estrogen on serotonin-related gene expression in marmosets. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Apr 3;58:71-80. doi: 10.1016/j.pnpbp.2014.11.008. Epub 2014 Dec 24. PMID: 25542371;PMCID: PMC4339406.

17: Bethea CL, Coleman K, Phu K, Reddy AP, Phu A. Relationships between androgens, serotonin gene expression and innervation in male macaques.Neuroscience. 2014 Aug 22;274:341-56. doi: 10.1016/j.neuroscience.2014.05.056.Epub 2014 Jun 5. PMID: 24909896; PMCID: PMC4109686.

18: Bethea CL, Kim A, Reddy AP, Chin A, Bethea SC, Cameron JL. Hypothalamic KISS1 expression,gonadotrophin-releasinghormone and neurotransmitter innervation vary with stress and sensitivity in macaques. J Neuroendocrinol.2014 May;26(5):267-81. doi: 10.1111/jne.12146. PMID: 24617839; PMCID:PMC4012296.

19: Bethea CL, Reddy AP. The effect of long-term ovariectomy on midbrain stress systems in free ranging macaques. Brain Res. 2012 Dec 7;1488:24-37. doi:10.1016/j.brainres.2012.09.035. Epub 2012 Oct 1. PMID: 23036275; PMCID:PMC3501558.

20: Senashova O, Reddy AP, Cameron JL, Bethea CL. The effect of citalopram on midbrain CRF receptors 1 and 2 in a primate model of stress-induced amenorrhea.Reprod Sci. 2012 Jun;19(6):623-32. doi: 10.1177/1933719111430992. Epub 2012 Mar12. PMID: 22412189; PMCID: PMC3439121.

21: Bethea CL, Reddy AP. Effect of ovarian steroids on gene expression related to synapse assembly in serotonin neurons of macaques. J Neurosci Res. 2012 Jul;90(7):1324-34. doi: 10.1002/jnr.23004. Epub 2012 Mar 13. PMID: 22411564;PMCID: PMC3350613.

22: Bethea CL, Reddy AP. Ovarian steroids increase glutamatergic related gene expression in serotonin neurons of macaques. Mol Cell Neurosci. 2012 Mar;49(3):251-62. doi: 10.1016/j.mcn.2011.11.005. Epub 2011 Nov 30. PMID:22154832; PMCID: PMC3306448.

 23: Reddy TP, Manczak M, Calkins MJ, Mao P, Reddy AP, Shirendeb U, Park B, Reddy PH. Toxicity of neurons treated with herbicides and neuroprotection by mitochondria-targeted antioxidant SS31. Int J Environ Res Public Health. 2011. Jan;8(1):203-21. doi: 10.3390/ijerph8010203. Epub 2011 Jan 19. PMID: 21318024;PMCID: PMC3037070.

24: Bethea CL, Reddy AP. Effect of ovarian hormones on genes promoting dendritic spines in laser-captured serotonin neurons from macaques. Mol Psychiatry. 2010Oct;15(10):1034-44. doi: 10.1038/mp.2009.78. Epub 2009 Aug 18. PMID: 19687787; PMCID: PMC3910421.

25: Bethea CL, Reddy AP, Pedersen D, Tokuyama Y. Expression profile of differentiating serotonin neurons derived from rhesus embryonic stem cells and comparison to adult serotonin neurons. Gene Expr Patterns. 2009 Feb;9(2):94-108.doi: 10.1016/j.gep.2008.10.002. Epub 2008 Nov 1. PMID: 18996226; PMCID:PMC2753257.

26: Bethea CL, Reddy AP. Effect of ovarian hormones on survival genes in laser captured serotonin neurons from macaques. J Neurochem. 2008 May;105(4):1129-43. doi: 10.1111/j.1471-4159.2008.05213.x. Epub 2008 Jan 7. PMID: 18182058.

27: Centeno ML, Reddy AP, Smith LJ, Sanchez RL, Henderson JA, Salli NC, Hess DJ, Pau FK, Bethea CL. Serotonin in microdialysate from the mediobasal hypothalamusincreases after progesterone administration to estrogen primed macaques. Eur J Pharmacol. 2007 Jan 19;555(1):67-75. doi: 10.1016/j.ejphar.2006.10.027. Epub2006 Oct 19. PMID: 17112509; PMCID: PMC1794103.

28: Sanchez RL, Reddy AP, Centeno ML, Henderson JA, Bethea CL. A second tryptophan hydroxylase isoform, TPH-2 mRNA, is increased by ovarian steroids in the raphe region of macaques. Brain Res Mol Brain Res. 2005 Apr 27;135(1-2):194-203. doi: 10.1016/j.molbrainres.2004.12.011. PMID: 15857682.

29: Salli U, Reddy AP, Salli N, Lu NZ, Kuo HC, Pau FK, Wolf DP, Bethea CL. Serotonin neurons derived from rhesus monkey embryonic stem cells: similarities to CNS serotonin neurons. Exp Neurol. 2004 Aug;188(2):351-64. doi: 10.1016/j.expneurol.2004.04.015. PMID: 15246835. 

30: Reddy AP, Bethea CL. Preliminary array analysis reveals novel genes regulated by ovarian steroids in the monkey raphe region. Psychopharmacology (Berl). 2005 Jun;180(1):125-40. doi: 10.1007/s00213-005-2154-1. Epub 2005 Feb25. PMID: 15731897.

Areas of Expertise

Technical and Scientific Strengths:

1. Mastered most of the molecular biology techniques such as as PCR, RT-PCR, genotyping, cDNA and RNA synthesis cloning, RFLP analysis, microRNA, circulating RNA and cloning and sub-cloning.
2. I have an extensive experience in global gene expression analysis with primate tissue, postmortem tissues, paraformaldehyde perfused tissues, Celli lines rodent tissues, a single cell from laser captured cells, and differentiated stem cells.
3. I have a strong background in histology, sectioning of frozen tissues, Immuno-cyto/histochemistry, and in situ hybridization, imaging and laser capture micro-dissection.
4. Proteins analysis using ELISA, Western, and some knowledge of HPLC mass spectrophotometry. Designed ELISA assays relevant to the cell-based analysis, tissue, plasma, and serum-based assay.
5. I have sound knowledge of bioinformatics and secure experience analyzing gene expression analysis data and present in contained format to relevant interpretation. 
6. I have strong background in cell culture, primary neurons, cell lines, stem cell differentiation using embryonic stem cells of human and rhesus macaques (clonal populations). Experience in cell-based assay apoptosis, viability, Seahorse analysis of cell metabolism, respiration rates, and cell phenotyping.
7. I have experience in writing a research protocols, designing significant research in primates and rodent, experience in quality control analysis, standardizing products, designing new protocols.
8. I have experience in rodent research as animal treatment, upbringing, and behavior analysis using multiple tests.
9. I have experience working with elementary to high school summer interns. Training undergrad and grad students, designing clinical research pilot studies, and help the clinicians to submit their clinical grants.