OHSU

P. Hemachandra Reddy

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. With such a large, aged population poised to be afflicted, AD has become a major health concern for society. Early detection, prevention, and therapeutic interventions are urgently needed for this devastating mental illness. Gene mutations are known to be the cause for less than 2% of total AD patients ("familial AD"), and causal factors are still unknown for the vast majority of AD patients ("late-onset"). Aging is considered the number one risk factor for the development of late-onset and familial AD. Several cellular mechanisms are reported to be involved in AD pathogenesis. However, mitochondrial oxidative stress and synaptic damage stand out as early events in AD progression. 

The focus of research in Dr. Reddy's lab is on understanding the molecular and cellular bases of aging and age-related neurodegenerative diseases, such as AD.  Currently, the Reddy lab is investigating the roles of amyloid beta (Aβ), synaptic pathology, and mitochondrial oxidative damage in the development and progression of AD. In a recent time-course, global gene-expression study in the amyloid beta precursor protein (AβPP) transgenic mouse model, Reddy and colleagues 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, Reddy and colleagues demonstrated amyloid beta association with mitochondria in AD neurons, and mitochondrial-amyloid beta is responsible for generating reactive oxygen species, mitochondrial dysfunction, and synaptic damage.  Recently, Reddy and colleagues, for the first time demonstrated that amyloid beta interacts with mitochondrial fission protein dynamin-related protein 1 (Drp1), induces excessive GTPase enzymatic activity, and that increased GTPase activity causes excessive mitochondrial fragmentation and abnormal mitochondrial distribution in neurons affected by AD.  Reddy lab also demonstrated oligomeric amyloid beta-induced impaired axonal transport of mitochondria and synaptic degeneration and neuronal death in primary neurons derived from APP transgenic mice.

Currently, Reddy and colleagues are investigating whether mitochondrial dysfunction triggers mitochondrial gene expression, and whether mutant APP and Aβ cause oxidative damage, synaptic pathology and cognitive deficits in AD mice.  Reddy and colleagues are also investigating whether mitochondrially targeted antioxidants (MTAs) reduce oxidative damage and Aβ pathology, increase neurite outgrowth and ameliorate cognitive deficits in AβPP transgenic mice. This project is being conducted in two ways in order to study mitochondrial function/dysfunction, Aβ pathology, cognitive behavior and extended lifespan: (1) by treating AβPP mice with MTAs and (2) by genetic crossing of AβPP mice with mitochondria-targeted catalase transgenic mice (MCAT mice that survive 5 months beyond normal, wild-type mice) if any, in AβPP mice treated with MTAs, and also in AβPP mice crossed with MCAT mice (double transgenic mice) relative to AβPP mice.

 

Further, Reddy lab is also investigating the mechanisms of transport of mutant huntingtin oligomers into nucleus and other subcellular organelles in neurons affected by Huntington's disease (HD).  Using primary neurons from transgenic mouse models of Aging, AD and HD and live-cell imaging tools, Reddy and colleagues are extensively investigating axonal transport of organelles, including mitochondria, mitochondrial biogenesis, mitochondrial dynamics (fission and fusion balance) and synaptic activity.  Further, using primary neurons/mammalian cells and high throughput screening tools, the Reddy lab is also screening the small molecule libraries in order to determine the molecules that protect neurons from patients with AD, HD and other neurodegenerative diseases.

 

BIOGRAPHY

P. Hemachandra Reddy is an associate scientist in the Division of Neuroscience. He is also a faculty member of the Neuroscience Graduate Program. He received his B.Sc. and M.Sc. in biology from Sri Venkateswara University, Tirupati, India. He received an M.Phil in human cytogenetics from Delhi University. He was a commonwealth scholar (1990-1993) before receiving his Ph.D. (1994) in human genetics from London University. He did his postdoctoral training (1995-2000) at the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD. After his postdoctoral training, he joined the OHSU-Neurological Sciences Institute Faculty in July 2000, and joined the center in July 2008.  Dr. Reddy has served as a standing member of the Veteran Affairs Merit Review Study Section, and also served on NIH study sections, including CDIN and NOMD.  Currently, Dr. Reddy is an associate/academic editor for 6 journals, and an editorial board for 20 journals.

 

KEY PUBLICATIONS

Mao P, Gallagher P, Nedungadi S, Manczak M, Shirendeb UP, Kohama SG, Ferguson  B, Park BS, Reddy PH (2012). Mitochondrial DNA deletions and differential mitochondrial  DNA content in Rhesus monkeys: Implications for aging. Biochim Biophys Acta. 1822, 111-119.

Calkins MJ, Manczak M, Mao P, Shirendeb U, 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.

Shirendeb UP, Calkins MJ, Manczak M, Anekonda V, Dufour B, McBride JL, Mao P, Reddy PH (2012). Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease. Hum Mol Genet. 21, 406-420.

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.

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. 

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.

Reddy PH (2011). Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer's disease. Brain Res. 1415, 136-148. 

 

See a full listing of Dr. Reddy's publications.