Alzheimer's disease (AD) and related neurodegenerative disorders are a major source of morbidity and mortality, particularly with the increasingly aged population of the United States. Pathology involving the microtubule-associated protein tau is a common feature of many such diseases, including AD, frontotemporal lobar degeneration, many forms of Parkinsonism, and amyotrophic lateral sclerosis. This proposal describes a training plan for the development of an academic neurologist interested in the molecular mechanisms of dementing diseases, particularly tau. The research plan focuses on the role of tau in AD pathology testing the hypothesis that tau is critical for the neuronal dysfunction induced by amyloid-beta (Abeta) in amyloid precursor protein (APP) transgenic mice. Preliminary studies indicate that tau removal prevents most behavioral and pathological abnormalities in APP mice at 4-7 months of age.
Specific Aim 1 extends this observation, studying older APP mice to examine how long the effects of Abeta remain tau-dependent and determining the effect of changing tau expression after AD is produced and dysfunction is apparent.
Specific Aim 2 considers signaling pathways that might mediate interactions between Abeta and tau, with an emphasis on the tyrosine kinase Fyn.
Specific Aim 3 studies downstream mechanisms for tau's role, specifically regulation of axonal transport and APP processing. The candidate has a Ph.D. in neuroscience and an M.D. with residency training in neurology. He is committed to a career in academic medicine studying the basic mechanisms of neurodegenerative diseases. To that end, the research proposal and career development plan build on his prior training in basic neuroscience, biochemistry, electrophysiology, and clinical neurology to provide expertise in transgenic mouse models, behavioral analysis, histology, and viral vectors. Dr. Lennart Mucke, who specializes in transgenic mouse models of neurodegenerative disease, is the candidate's sponsor. The mentoring and research experience described in this proposal will facilitate the candidate's goal of an independent faculty research position.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS054811-06
Application #
7800397
Study Section
NST-2 Subcommittee (NST)
Program Officer
Corriveau, Roderick A
Project Start
2006-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
6
Fiscal Year
2010
Total Cost
$174,809
Indirect Cost
Name
University of Alabama Birmingham
Department
Neurology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Filiano, Anthony J; Martens, Lauren Herl; Young, Allen H et al. (2013) Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice. J Neurosci 33:5352-61
Fernandez, Hubert H; Vanagunas, Arvydas; Odin, Per et al. (2013) Levodopa-carbidopa intestinal gel in advanced Parkinson's disease open-label study: interim results. Parkinsonism Relat Disord 19:339-45
Hall, Alicia M; Roberson, Erik D (2012) Mouse models of Alzheimer's disease. Brain Res Bull 88:3-12
Palop, Jorge J; Roberson, Erik D; Cobos, Inma (2011) Step-by-step in situ hybridization method for localizing gene expression changes in the brain. Methods Mol Biol 670:207-30
Roberson, Erik D; Halabisky, Brian; Yoo, Jong W et al. (2011) Amyloid-ýý/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci 31:700-11
Roberson, Erik D (2011) Contemporary approaches to Alzheimer's disease and frontotemporal dementia. Methods Mol Biol 670:1-9
Palop, Jorge J; Mucke, Lennart; Roberson, Erik D (2011) Quantifying biomarkers of cognitive dysfunction and neuronal network hyperexcitability in mouse models of Alzheimer's disease: depletion of calcium-dependent proteins and inhibitory hippocampal remodeling. Methods Mol Biol 670:245-62
Jun, Gyungah; Naj, Adam C; Beecham, Gary W et al. (2010) Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67:1473-84
Rabinovici, Gil D; Roberson, Erik D (2010) Beyond diagnosis: what biomarkers are teaching us about the ""bio""logy of Alzheimer disease. Ann Neurol 67:283-5
Wacker, Jennifer L; Huang, Shao-Yi; Steele, Andrew D et al. (2009) Loss of Hsp70 exacerbates pathogenesis but not levels of fibrillar aggregates in a mouse model of Huntington's disease. J Neurosci 29:9104-14

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