A fundamental question remains unresolved regarding the significance of the increased levels of basic Fibroblast Growth Factor (bFGF) which we have observed in Alzheimer's disease. Is this increase an active process that enhances Beta/A4 amyloid deposition and occurs as a function of age-related growth factor dysregulation; or is this increase a passive process which results from the intrinsic tendency of bFGF and possibly the other newly identified heparin-binding growth factors, to bind to the heparan-sulfate proteoglycans recently shown to be associated with Beta/A4 amyloid deposition? The proposed studies will use a carefully planned comprehensive post-mortem study of control and Alzheimer brains to test the following hypotheses: 1) Abnormalities in heparin-binding growth factors correlate with the severity of Alzheimer's disease pathology; 2) Heparin-binding growth factors are altered early in the course of disease and precede the appearance of Beta/A4 amyloid-containing senile plaques; 3) Heparin-binding growth factors increase as a function of the normal aging process. Biochemical and morphologic analyses of tissues obtained from the same brain regions will be performed in order to compare the findings in five representative brain regions severely affected by Alzheimer's disease with five representative regions that are typically spared by the disease process. The proposed studies will include: a) qualitative immunocytochemical analyses of basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial growth factor (VEGF) and heparin binding neurotrophic factor (HBNF); b) qualitative analyses of the distribution of bFGF, aFGF, VEGF and HBNF mRNA hybridization signal density; c) quantitative protein assays for bFGF, aFGF, VEGF and HBNF (RIA and Western analyses); and d) morphometric analyses of senile plaque, neurofibrillary tangle and reactive astrocyte counts/mm2. The morphologic and biochemical alterations observed in 20 patients with early Alzheimer's disease will be compared to 20 patient with advanced Alzheimer's disease, as well as to their respective age, sex, and post-mortem interval matched controls. In addition, we will examine possible heparin binding growth factor abnormalities which may occur as a function of the normal aging process by assessing these same parameters in patients who expire during the 3rd, 6th and 9th decades. Current evidence suggests that basic fibroblast growth factor may be an important neurotrophic factor in the adult central nervous system. The data obtained from these studies will provide new insights that are essential in designing heparin-binding growth factor treatment strategies for Alzheimer's disease. An active relationship to Beta/A4 amyloid deposition would suggest a need for the utilization of heparin-binding growth factor antagonists. Alternatively, a passive relationship to Beta/A4 amyloid deposition would necessitate the use of heparin-binding growth factor supplementations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG010682-01
Application #
3122629
Study Section
Special Emphasis Panel (SRC (33))
Project Start
1991-09-29
Project End
1996-06-30
Budget Start
1991-09-29
Budget End
1992-06-30
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Johanson, Conrad; Stopa, Edward; McMillan, Paul et al. (2011) The distributional nexus of choroid plexus to cerebrospinal fluid, ependyma and brain: toxicologic/pathologic phenomena, periventricular destabilization, and lesion spread. Toxicol Pathol 39:186-212
Famiglietti, Edward V; Stopa, Edward G; McGookin, Edward D et al. (2003) Immunocytochemical localization of vascular endothelial growth factor in neurons and glial cells of human retina. Brain Res 969:195-204
Johanson, C E; Jones, H C; Stopa, E G et al. (2002) Enhanced expression of the NA-K-2 Cl cotransporter at different regions of the blood-CSF barrier in the perinatal H-Tx rat. Eur J Pediatr Surg 12 Suppl 1:S47-9
Stopa, E G; Volicer, L; Kuo-Leblanc, V et al. (1999) Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. J Neuropathol Exp Neurol 58:29-39
Kim, K H; Patel, L; Tobet, S A et al. (1999) Gonadotropin-releasing hormone immunoreactivity in the adult and fetal human olfactory system. Brain Res 826:220-9
Donahue, J E; Berzin, T M; Rafii, M S et al. (1999) Agrin in Alzheimer's disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma. Proc Natl Acad Sci U S A 96:6468-72
Fenton, H; Finch, P W; Rubin, J S et al. (1998) Hepatocyte growth factor (HGF/SF) in Alzheimer's disease. Brain Res 779:262-70
Schipper, H M; Liberman, A; Stopa, E G (1998) Neural heme oxygenase-1 expression in idiopathic Parkinson's disease. Exp Neurol 150:60-8
Tobet, S A; Chickering, T W; King, J C et al. (1996) Expression of gamma-aminobutyric acid and gonadotropin-releasing hormone during neuronal migration through the olfactory system. Endocrinology 137:5415-20
Schipper, H M; Cisse, S; Stopa, E G (1995) Expression of heme oxygenase-1 in the senescent and Alzheimer-diseased brain. Ann Neurol 37:758-68

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