2006 Awardee
P. Hemachandra Reddy, Ph.D.

P. Hemachandra Reddy was a commonwealth scholar (1990-1993) before receiving his Ph.D. (1994) from University College , London University . He did his postdoctoral training (1995-2000) with Dr. Danilo A. Tagle at the National Human Genome Research Institute, National Institutes of Health, Bethesda , MD. In his post-doctoral research, Dr. Reddy isolated and characterized cDNAs containing polymorphic polyglutamine (CAG)n repeats in the adult human brain cDNA library. In 1998, Dr. Reddy was the first researcher to develop a transgenic mouse model for Huntington's disease (HD) using full-length HD cDNA. This mouse model showed progressive phenotypic behavior and selective neurodegeneration in the striatum and cortex. After his postdoctoral training, Dr. Reddy joined the Neurological Sciences Institute Faculty at Oregon Health & Science University (OHSU) in July 2000 and established the OHSU Neurogenetics Laboratory. The research focus in the Reddy laboratory is on understanding molecular and cellular bases of neurodegenerative diseases. Currently, the Reddy laboratory is focusing on unraveling the connection between amyloid-β (Aβ) and synaptic damage, and Aβ and mitochondrial oxidative damage in Alzheimer's disease (AD).Dr. Reddy is studying synaptic pathology, mitochondrial oxidative damage, and the association of synaptic damage and mitochondrial dysfunction with cognitive decline in AD, using AD postmortem brain specimens, AD transgenic mouse models (Tg2576 mice, AβPP/PS1 mice, and AβPP/PS1/Tau mice), AβPP cell models, state-of-the art gene expression techniques, and molecular and biochemical methods. In addition to standard molecular and cell biology techniques, the Reddy laboratory has established quantitative real-time PCR technique in combination with Sybr-green chemistry, fluorescently labeled in situ hybridization and immunofluorescence analysis techniques. Dr. Reddy has successfully applied these techniques in numerous studies to determine differentially expressed mitochondrial genes, the cellular localization of mitochondrial mRNAs, and their association with mitochondrial dysfunction in AD patients and AD transgenic models. Recently, the Reddy laboratory demonstrated an association of Aβ with mitochondria in AD transgenic (Tg2576 mice) and mouse neuroblastoma (N2a) cells expressing human mutant AßPP. Further, Dr. Reddy and his colleagues have demonstrated that in Tg2576 mice, mitochondrial Aβ induces free radical production, decreases cytochrome c oxidase activity, and increases carbonyl proteins during disease development and progression.

Importance of Published Article
Members of the Reddy laboratory performed the research presented in the paper “ Differential loss of synaptic proteins in Alzheimer's disease: Implications for synaptic dysfunction” (JAD 7:103-117, 2005). Synaptic pathology is a prominent feature of AD and strongly correlates with cognitive impairments. Synaptic damage occurs early in AD development, suggesting that synaptic alterations are a primary event in the progression of AD. However, the underlying mechanisms of synaptic pathology in AD are not completely understood. The degree of cognitive decline in patients with AD has been correlated with changes in the presynaptic vesicle protein ‘synaptophysin' in the hippocampus and the associated cortices. However, it remains unclear how synaptic organization, including presynaptic, postsynaptic, and synaptic membrane proteins, is altered in AD patients.

The main objective of the research awarded the prize was to determine whether presynaptic or postsynaptic compartments of neurons in AD patients are preferentially affected by disease. Using immunoblotting, immunocytochemistry, and densitometry techniques, Reddy and his colleagues investigated 3 presynaptic vesicle proteins (synaptophysin, synaptotagmin, and Rab 3A), 2 presynaptic membrane proteins (GAP 43 and synaptobrevin), and 2 postsynaptic proteins (neurogranin and synaptopodin) in a large number of postmortem brains from AD patients and age-matched control subjects. They found a selective loss of both presynaptic and post synaptic proteins in the postmortem brains from the AD patients relative to those from the age-matched control subjects. Of the 7 synaptic proteins studied, the presynaptic proteins synaptophysin and rab 3A, and the postsynaptic protein synaptopodin were the most down-regulated. In addition, this paper is the first to report on the loss of synaptopodin in the postmortem brains from AD patients – a finding that beckons further investigation of postsynaptic proteins in AD patients.