This proposal for a LEAD award has the participation of Paul D. Coleman as the senior investigator and three junior investigators at the Assistant Professor level. In addition four Pilot Proposals are presented. The bulk of the studies proposed revolve around neuron death and neuronal plasticity. Thus, Coleman hypothesizes that AD represents a defect in the normal ability of neurons in some regions of the ages brained to mount a plastic, compensatory response to death of their neighbors. He proposes a model whereby glia serve as intermediaries in modulating the responses of surviving neurons to death of their neighbors. Coleman proposes to use neurobiological, tissue culture, molecular and protein methods in postmortem human brain, experimental rodent brain and in vitro model systems to test the hypothesis of defective plasticity in the AD brain, to test the proposed model and isolate proteins that may serve the signaling functions called for by the model. Higgins hypothesizes that the amyloid pathology of AD is related to deficits in the NGF responsiveness of basal forebrain cholinergic neurons, and he proposes molecular studies to determine whether NGF receptor (NGF-R) gene expression is altered in the basal forebrain in AD, whether expression of a specific form of the amyloid precursor protein (APP) may be altered in the basal forebrain in AD, and whether any changes in expression of forms of APP may relate to NGF responsiveness. Richfield proposes that dopamine systems play a significant role in some forms of dementia, and that defects in plasticity of dopamine neurons may be important to some dementias. He proposes to examine the dopaminergic system in both human and animal models. Slemmon hypothesizes that peptide expression is altered in AD, and he presents preliminary evidence for differential expression of two peptides in the frontal cortex of the AD brain. These peptides do not appear to correspond to any peptides currently known to be expressed at altered levels in AD. He proposes to confirm the differential expression of these peptides, sequence them and make antibodies to them. From sequence he hopes to find regions of homology with sequences with known functions. With antibodies he will determine which cells contain the peptide and their regional distribution in normal aging and AD. These forms of information should give some initial insights into functions of these peptides. He also proposes to determine whether there are other peptides which are also differentially expressed in AD. Pilot Projects are proposed which relate to: The expression of message for microtubule- associated protein, Map 2, in aging and AD brain; Regulation of expression of c-fos in vasopressin neurons in aging; hippocampal glucocorticoid receptors in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Unknown (R35)
Project #
5R35AG009016-04
Application #
3478947
Study Section
Aging Review Committee (AGE)
Project Start
1990-05-01
Project End
1997-04-30
Budget Start
1993-05-20
Budget End
1994-04-30
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Richfield, Eric K; Vonsattel, Jean-Paul; MacDonald, Marcy E et al. (2002) Selective loss of striatal preprotachykinin neurons in a phenocopy of Huntington's disease. Mov Disord 17:327-32
Callahan, Linda M; Vaules, William A; Coleman, Paul D (2002) Progressive reduction of synaptophysin message in single neurons in Alzheimer disease. J Neuropathol Exp Neurol 61:384-95
Chang, J W; Young, D A; Coleman, P D et al. (2001) Two-dimensional gel analysis of secreted proteins induced by interleukin-1 beta in rat astrocytes. Neurochem Int 39:349-59
Yao, P J; Weimer, J M; O'Herron, T M et al. (2000) Clathrin assembly protein AP-2 is detected in both neurons and glia, and its reduction is prominent in layer II of frontal cortex in Alzheimer's disease. Neurobiol Aging 21:921-9
Yermakova, A; O'Banion, M K (2000) Cyclooxygenases in the central nervous system: implications for treatment of neurological disorders. Curr Pharm Des 6:1755-76
Utal, A K; Coleman, P D (1999) Non-HPLC separation of water-soluble choline metabolites by two-dimensional high voltage electrophoresis and thin layer chromatography. J Neurosci Methods 90:13-21
Yermakova, A V; Rollins, J; Callahan, L M et al. (1999) Cyclooxygenase-1 in human Alzheimer and control brain: quantitative analysis of expression by microglia and CA3 hippocampal neurons. J Neuropathol Exp Neurol 58:1135-46
Morsch, R; Simon, W; Coleman, P D (1999) Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol 58:188-97
Callahan, L M; Vaules, W A; Coleman, P D (1999) Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. J Neuropathol Exp Neurol 58:275-87
Yao, P J; Morsch, R; Callahan, L M et al. (1999) Changes in synaptic expression of clathrin assembly protein AP180 in Alzheimer's disease analysed by immunohistochemistry. Neuroscience 94:389-94

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