P. Hemachandra Reddy

Currently, 4.5 million Americans suffer from Alzheimer’s disease (AD). The disease usually starts after age 60, and risk increases with age. It is estimated that by the year 2050, 50% of people worldwide who are 85 years of age will be afflicted with AD. With such a large aged population poised to be afflicted, AD has become a major health concern in the society. Early detection, prevention, and therapeutic interventions are urgently needed for this devastating mental illness. Gene mutations are known to be the cause for a small proportion (less than 2%) of total AD patients, and causal factors are still unknown for the vast majority of AD patients. Aging is considered ‘the number one risk factor’ for the development of late-onset and familial AD. Several cellular mechanisms are reported to involve in AD pathogenesis. However, the mitochondrial oxidative stress and synaptic damage have recently been reported as early events in AD progression. 

The research focus in the Reddy lab is on understanding molecular and cellular bases of aging and age-related neurodegenerative diseases, particularly 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 of amyloid precursor protein (APP) transgenic mice, Reddy and colleagues found that the genes related to mitochondrial energy metabolism and apoptosis were upregulated in 2-, 5- and 18-month-old APP mice compared to age-matched wild-type mice, suggesting that mitochondrial energy metabolism might be impaired by mutant APP and Aβ and that the upregulation of mitochondrial genes might be a compensatory response. Further, Reddy and colleagues found that a 4kDa Aβ in isolated mitochondria from the cerebral cortex of APP transgenic mice and in isolated mitochondria from N2a cells expressing APP, and is responsible for generating reactive oxygen species, mitochondrial dysfunction, and synaptic damage in AD neurons. Currently, Reddy and colleagues are investigating to determine whether mitochondrial dysfunction triggers mitochondrial gene expression, and also to determine whether mutant APP and Aβ cause oxidative damage, synaptic pathology and cognitive deficits in AD mice.

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

In another project, the Reddy lab is studying the mitochondrial DNA changes and mitochondrial dynamics (fission and fusion balance) in the brains of male and female, and young and aged nonhuman primates, laboratory mice and humans, in order to determine the effect of age and gender in mitochondrial structure and function, and cell survival and cell death.

BIOGRAPHY

P. Hemachandra Reddy is an assistant scientist in the Division of Neuroscience and an  assistant professor in the Department of Physiology and Pharmacology. 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. 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.

KEY PUBLICATIONS

Manczak M, Park BS, Jung Y, and Reddy PH. (2004) Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med. 5:147-162. PMID:15075441.

Reddy PH, McWeeney S, Park BS, Manczak M, Gutala RV, Partovi D, Jung Y, Yau V, Searles R, Mori M and Quinn J. (2004) Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. Hum Mol Genet. 13:1225-1240. PMID:15115763.

Reddy PH, Mani G, Park BS, Jacques J, Murdoch G, Whetsell W Jr, Kaye J and Manczak M. (2005) Differential loss of synaptic proteins in Alzheimer's disease: implications for synaptic dysfunction. J Alzheimers Dis. 7:103-117. PMID:15851848.

Manczak M, Anekonda TS, Henson E, Park BS, Quinn JF, and Reddy PH. (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 15:1437-1449. PMID:16551656.

Reddy PH (2006) Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease. J Neurochem. 96:1-13. PMID:16305625.

Reddy, PH and Beal MF. (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med. 14:45-53. PMID:18218341.

Reddy PH. (2008) Mitochondrial medicine for aging and neurodegenerative disease. Neuromolecular Medicine. 10:291-315. PMID:18566920.