TTUHSC School of Medicine
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P. Hemachandra Reddy, Ph.D.

P. Hemachandra Reddy, Ph.D.

Professor
Executive Director, Garrison Institute on Aging

Ph.D. Human Genetics
University College London, London University, 1994
Curriculum Vitae

Cell Biology and Biochemistry, Neuroscience/Pharmacology, and Neurology
Texas Tech University Health Sciences Center
3601 4th Street
Lubbock, TX 79430
Phone: (806) 743-2385

hemachandra.reddy@ttuhsc.edu


Research Interests

Aging, Neurodegenerative diseases - Alzheimer’s, Huntington’s, Parkinson’s and multiple sclerosis, Mitochondria, Oxidative Stress, Diabetes/Obesity, Gene Expression Analysis and Gender-based neuronal changes.

To learn more, visit:

Garrison Institute on Aging: www.ttuhsc.edu/aging

Current Projects

Amyloid Beta, Synaptic Pathology, and Mitochondrial Dysfunction in Alzheimer's Disease
Currently, 5.4 million Americans suffer from Alzheimer’s disease (AD). The disease usually starts after age 60, and the risk of AD onset increases with age. It is estimated that by the year 2050, 50% of people worldwide who are 85 years of age and older will be afflicted with AD. Two-thirds of women and one-third of men are at lifetime risk for AD. Despite tremendous progress in AD research, there is still no clear understanding of why more women than men are at risk for AD, and there are still no early detectable markers and drugs/agents that can delay and/or prevent AD in either men or women. Aging is considered the number one risk factor for the development of late-onset AD. Several cellular mechanisms are reported to be involved in AD pathogenesis. However, mitochondrial dysfunction and synaptic damage stand out as early events in AD progression. 

In a time-course, global gene-expression study using the amyloid beta precursor protein (AβPP) transgenic mouse model, we found that the genes related to mitochondrial energy metabolism and apoptosis were up-regulated in 2-, 5- and 18-month-old AβPP mice compared to age-matched wild-type mice.  These results suggest that mitochondrial energy metabolism might be impaired by mutant APP and Aβ, and that the up-regulation of mitochondrial genes may be a compensatory response to this impairment. Further, we found Aβ to be associated with mitochondria in AD neurons and is responsible for generating reactive oxygen species, mitochondrial dysfunction, and synaptic damage, all of which have been implicated in AD pathogenesis.  For the first time, we demonstrated that Aβ interacts with the mitochondrial fission protein Drp1, induces excessive GTPase enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal mitochondrial distribution in AD neurons.  Further, recently, we found that mitochondrial permeability transition pore protein, VDAC1 interacts with Aβ and phosphorylated tau and causes mitochondrial damage in neurons affected by AD. Currently, we are investigating the physiological relevance of these abnormal interactions in disease process and also trying to develop molecular inhibitors to reduce Aβ- and phosphorylated tau-induced neuronal toxicities in AD progression.

Mitochondria-targeted Molecules and Alzheimer’s Disease Therapeutics
In a mitochondrial therapeutics project, my lab is investigating whether mitochondria-targeted molecules can reduce oxidative damage and Aβ pathology, increase neurite outgrowth, and ameliorate cognitive deficits in AβPP transgenic mice. To study mitochondrial function/dysfunction, Aβ pathology, cognitive behavior, and the lifespan, we are: (1) treating AβPP mice with mitochondria-targeted molecules and (2) we are crossing AβPP mice with mitochondria-targeted catalase transgenic mice (MCAT mice, which are known to survive 5 months longer than normal, wild-type mice), if any, in AβPP mice treated with mitochondria-targeted molecules, and also in AβPP mice crossed with MCAT mice (double transgenic mice) relative to AβPP mice.

Mutant Huntingtin, Mitochondrial Dynamics, and Huntington’s Disease
Using postmortem brains from patients with Huntington's disease and from transgenic mice with Huntington’s disease (HD), we are exploring the role of abnormal mitochondrial dynamics in the progression of HD.  Using primary neurons from transgenic mouse models of HD, state-of-the-art, live-cell imaging tools, and transmission electron microscopy, my lab is investigating axonal transport of mitochondria, mitochondrial biogenesis, mitochondrial dynamics (e.g., fission and fusion balance), and synaptic activity.  Further, studying primary neurons and mammalian cells with high throughput screening tools, my lab is screening small molecule libraries in order to identify the molecules that protect neurons in patients with HD and other neurodegenerative diseases.

Experimental Therapeutics of Multiple Sclerosis
Oxidative stress and mitochondrial dysfunction are involved in the progression and pathogenesis of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) mouse model and the mitochondria-targeted molecule MitoQ, my lab is studying the beneficial effects of MitoQ in EAE mice (mice that mimic MS symptoms). Initial findings are revealing that pretreatment and treatment of EAE mice with MitoQ reduce neurological disabilities associated with EAE and lead to significantly suppressed inflammatory markers of EAE, including the inhibition of inflammatory cytokines and chemokines. Currently, my lab is exploring the neuroprotective mechanisms of MitoQ in EAE mice and also preparing to study the effects of MitoQ on MS patients in a series of clinical trials.


Selected Publications

  • Reddy PH (2014) Increased Mitochondrial Fission, Synaptic Damage, and Neuronal Dysfunction in Huntington's Disease: Implications for Molecular Inhibitors of Excessive Mitochondrial Fission. Drug Discovery Today. 19, 951-955. PubMed
  • Mao P, Manczak M, Shirendeb UP and Reddy PH (2013) MitoQ, a mitochondria-targeted antioxidant delays disease progression and extends lifespan in an experimental autoimmune encephalomyelitis mouse model of Multiple Sclerosis. Biochim Biophys Acta 1832, 2322-2331.
  • Mao P, Manczak M, Calkins MJ, Troung Q, Reddy TP, Reddy AP, Shirendeb UP, Lo HH, Rabinovitch Reddy PH (2012) Mitochondria-targeted catalase reduces abnormal APP processing, amyloid beta production, and BACE1 in a mouse model of Alzheimer’s disease: Implications for neuroprotection and lifespan extension. Hum Mol Genet 21, 2973-2990. PubMed
  • Manczak M, Reddy PH (2012). Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet. 21, 2538-2547. PubMed
  • Reddy PH, Tripathi R, Troung Q, Tirumala K, Reddy TP, Anekonda V, Shirendeb UP, Calkins MJ, Reddy AP, Mao P, Manczak M (2012). Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: Implications to mitochondria-targeted antioxidant therapeutics. Biochim Biophys Acta. 1822, 639-639. PubMed
  • Shirendeb UP, Calkins M, Manczak M, Anekonda V, Dufour B, McBride J, Mao P and Reddy PH (2012) Mutant huntington’s association with mitochondria protein Drp1, and impaired axonal transport of mitochondria in Huntington’s disease neurons. Hum Mol Genet 21, 406-420. PubMed
  • Calkins MJ, Manczak M, Mao P, Shirendeb U and Reddy PH (2011) Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer’s disease. Hum Mol Genet 20, 4515-4529.
  • Reddy PH (2011) Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria,n and synaptic deprivation in Alzheimer's disease. Brain Res 1415:136-148. PubMed
  • Manczak M, Calkins MJ, Reddy PH (2011) Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. Hum Mol Genet 20, 2495-2509. PubMed
  • Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA, Reddy PH (2011) Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage. Hum Mol Genet 20, 1438-1455. PubMed
  • Reddy PH, Reddy TP, Manczak M, Calkins MJ, Shirendeb U, Mao P (2011) Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases. Brain Res Rev 67, 103-118. PubMed
  • Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, M Murphy, HH Szeto, Park BS, Reddy PH (2010) Mitochondria-targeted antioxidants protect against Abeta toxicity in Alzheimer’s disease neurons J. Alzheimer’s Disease 20 Suppl 2:S609-631. PubMed
  • Manczak M, Mao P, Nakamura K, Bebbington C, Park BS, Reddy PH (2009) Neutralization of granulocyte macrophage colony stimulating factor decreases Amyloid beta 1-42 and suppresses microglial activity in transgenic mouse model of Alzheimer’s Disease. Hum Mol Genet 18, 3876-3893. PubMed
  • Reddy PH and Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications to cognitive decline in aging and Alzheimer’s disease. Invited article by Trends in Molecular Medicine 14, 45-53 (Invited). PubMed
  • Manczak M, Anekonda TS, Park BS, Henson E, Quinn J, Reddy PH (2006). Mitochondria are a direct site of Aβ accumulation in Alzheimer’s disease: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15, 1437-1449. PubMed
  • Reddy PH (2006) Amyloid precursor protein mediated free radical generation: implications to development and progression of Alzheimer’s disease. Journal of Neurochemistry 96, 1-13. PubMed
  • Reddy PH, Mani G, Park BS, Jacques J, Murdoch G, Whetsell W. Jr., Kaye JA, Manczak (2005) Differential loss of synaptic proteins in Alzheimer’s disease: Implications for synaptic dysfunction. Journal of Alzheimer’s Disease 7, 103-117. PubMed
  • Reddy PH, McWeeney S, Manczak M, Park BS, Gutala RV, Jung Y, Yau V, Searles R, Mori M, Quinn J (2004) Gene expression profiles of transcripts in amyloid precursor protein transgenic Mice: Upregulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer’s disease. Published in Hum Mol Genet 13, 1225-1240. PubMed
  • Reddy PH, Williams M, Tagle DA (1999) Recent advances in understanding Huntington’s Disease pathogenesis. Trend Neurosci 22, 248-255. PubMed
  • Reddy PH, Williams M, Charles V, Garrett L, Buchanan LP, Whetsell, WO Jr, Miller G, Tagle DA (1998) Behavioral abnormalities and selective neuronal loss in transgenic mice expressing mutated full-length HD cDNA. Nat Genet 20, 198-202. PubMed
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