This Program has provided compelling evidence for a self amplifying cycle of interactions between neurons and glia, mediated largely by neuroinflammatory cytokines acting as drivers of Alzheimer's disease (AD) pathogenesis;chief among these is interleukin-1 (IL-1). We have focused on the entry points into this cycle, which is to say the early events in a given neuron's circuit of interactions with its local environs. Recent examinations of human tissue and of a newly acquired transgenic Alzheimer model indicate that pathology of the Alzheimer type is initially associated with neuronal elevation of apolipoprotein E (ApoE) and ?-amyloid precursor protein (?APP). Empirical studies in cell culture suggest that the ?APP/ApoE response in tissue is due to a causal relationship in which ?APP expression is dependent on co-expression of ApoE, with ApoE e3 more efficacious than ApoE e4, and is modulated by IL-1. Neuronal ?APP elevation is accompanied by secretion of ?APP fragments, which activate microglia and cause glutamate release. Together, this suggests that a glutamate-ApoE-?APP axis is initialized in the early neuronal responses to adverse stimuli and neuroinflammation. With these results, we were surprised to find that i) ?APP expression declines in neuronal somata as one approaches mature A? plaques, either temporally or spatially;and ii) glial activation persists in Alzheimer brain in the presence or following "clearance" of A? plaques. Together, these data inspire a hypothesis that unifies the current renewal of this Program: The typical acute-phase response of neurons to adverse stimuli is to elevate ApoE and ?APP expression via a coordinated, causal relationship between ApoE and ?APP expression that becomes uncoupled in AD pathogenesis, leaving neurons with insufficient ?APP and a propensity to make inappropriate cellular responses and to succumb to the excitotoxic stress perpetrated by "classical" activation of microglia. Human tissue and model systems will be used in Project 1 to identify and elucidate the basic elements of the glutamate-ApoE-?APP axis, and the role of IL-1 in its failure in AD. Project 2 will identify, in two unique populations, common pathways for microglial activation and cytokine release and the degree to which this activation is reflected in mRNA and protein expression profiles. Project 3 will investigate key aspects of microglial activation related to oxidative production of glutamate and the differential modulation of this activation by IL-1a gene polymorphisms. Three cores provide administrative coordination (Core A), tissue banking and processing (Core B), and molecular/biochemical sample analyses (Core C) for these studies. The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG012411-15
Application #
8247778
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (J2))
Program Officer
Refolo, Lorenzo
Project Start
1997-08-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
15
Fiscal Year
2012
Total Cost
$1,226,455
Indirect Cost
$330,788
Name
University of Arkansas for Medical Sciences
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Pey, Peixuan; Pearce, Ronald K B; Kalaitzakis, Michail E et al. (2014) Phenotypic profile of alternative activation marker CD163 is different in Alzheimer's and Parkinson's disease. Acta Neuropathol Commun 2:21
Kuang, Xiu-Li; Liu, Fang; Chen, Huifang et al. (2014) Reductions of the components of the calreticulin/calnexin quality-control system by proteasome inhibitors and their relevance in a rodent model of Parkinson's disease. J Neurosci Res 92:1319-29
Zhang, Hanying; Okamoto, Miyako; Panzhinskiy, Evgeniy et al. (2014) PKC?/midkine pathway drives hypoxia-induced proliferation and differentiation of human lung epithelial cells. Am J Physiol Cell Physiol 306:C648-58
Barger, Steven W (2013) Apolipoprotein E acts at pre-synaptic sites...among others. J Neurochem 124:1-3
Gentleman, S M (2013) Review: microglia in protein aggregation disorders: friend or foe? Neuropathol Appl Neurobiol 39:45-50
Wilcock, Donna M; Griffin, W Sue T (2013) Down's syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J Neuroinflammation 10:84
Kalaitzakis, M E; Gentleman, S M; Pearce, R K B (2013) Disturbed sleep in Parkinson's disease: anatomical and pathological correlates. Neuropathol Appl Neurobiol 39:644-53
Barger, Steven W (2013) TMEM106B and frontotemporal lobar degeneration: can over-expression tell us how reductions are beneficial? J Neurochem 126:696-8
Topchiy, Elena; Panzhinskiy, Evgeniy; Griffin, W Sue T et al. (2013) Nox4-generated superoxide drives angiotensin II-induced neural stem cell proliferation. Dev Neurosci 35:293-305
Wang, Wei; Barger, Steven W (2012) Cross-linking of serine racemase dimer by reactive oxygen species and reactive nitrogen species. J Neurosci Res 90:1218-29

Showing the most recent 10 out of 118 publications