Alzheimer's Disease (AD) is a degenerative disorder associated with deposits of plaques containing the protein beta amyloid. Although loss of cortical neurons, decreased synaptic connections, and marked reactive gliosis are prominent features of AD, the mechanisms to account for these histologic abnormalities remain uncertain. We believe that AD plaques are recognized as foreign bodies in the brain and elicit local microglial reactivity. Because of the size and chemical stability, these plaques are difficult to eliminate from CNS tissues and, therefore, persist as chronic irritants. We suggest that plaque-associated reactive microglia chronically release cytotoxic factors that cause cell death and gliosis in surrounding tissues. To investigate the ability of AD plaques to activate microglia, we will carry out quantitative neuropathologic studies of microglial subtypes and plaque classifications from AD brain obtained through autopsy. We will employ in vitro models to extend these observations by measuring plaque and beta amyloid effects upon cultured rat and human microglia. Endpoints will include altered morphology, up regulation of surface receptors, release of cellular modulators, and cytokinetic effects induced by plaques upon cultured microglia. In order to uncover the relationships between microglia and neuronal injury in AD, we will measure plaque-stimulated production of neuron-killing factors in vitro and the production of neuron-killing factors in human brain tissues. We will also explore the ability of plaques to elicit cell- contact injury of neurons. Major and minor protein constituents of amyloid deposits will be isolated by Dr. Alex Roger and used to assess the which components of native plaques drive microglial reactivity. Quantitative measures of neuroanatomic changes in AD brain using confocal scanning laser microscopy will help to elucidate reactive microglia associations with neuronal and synaptic loss. If successful, this proposed research will uncover fundamentally important signals and events which regulate immune-mediated mechanisms of brain injury in AD. Uncovering such mechanisms will be necessary in developing rational immunosuppressive strategies for treatment of dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
3P50AG008664-09S2
Application #
6295502
Study Section
Project Start
1999-06-01
Project End
2003-05-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Doody, R; Pavlik, V; Massman, Paul et al. (2005) Changing patient characteristics and survival experience in an Alzheimer's center patient cohort. Dement Geriatr Cogn Disord 20:198-208
Waring, Stephen C; Doody, Rachelle S; Pavlik, Valory N et al. (2005) Survival among patients with dementia from a large multi-ethnic population. Alzheimer Dis Assoc Disord 19:178-83
Hoyt, Brian D; Massman, Paul J; Schatschneider, Christopher et al. (2005) Individual growth curve analysis of APOE epsilon 4-associated cognitive decline in Alzheimer disease. Arch Neurol 62:454-9
Snow, A Lynn; Norris, Margaret P; Doody, Rachelle et al. (2004) Dementia Deficits Scale. Rating self-awareness of deficits. Alzheimer Dis Assoc Disord 18:22-31
Doody, Rachelle Smith; Dunn, J Kay; Huang, Eugene et al. (2004) A method for estimating duration of illness in Alzheimer's disease. Dement Geriatr Cogn Disord 17:1-4
Atchison, Timothy B; Bradshaw, Major; Massman, Paul J (2004) Investigation of profile difference between Alzheimer's disease patients declining at different rates: examination of baseline neuropsychological data. Arch Clin Neuropsychol 19:1007-15
Graham, David P; Cully, Jeffrey A; Snow, A Lynn et al. (2004) The Alzheimer's Disease Assessment Scale-Cognitive subscale: normative data for older adult controls. Alzheimer Dis Assoc Disord 18:236-40
Clark, Christopher M; Xie, Sharon; Chittams, Jesse et al. (2003) Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol 60:1696-702
Davis, Robert N; Massman, Paul J; Doody, Rachelle S (2003) WAIS-R factor structure in Alzheimer's disease patients: a comparison of alternative models and an assessment of their generalizability. Psychol Aging 18:836-43
Davis, Robert N; Massman, Paul J; Doody, Rachelle S (2003) Effects of blood pressure on neuropsychological functioning in Alzheimer's disease. Arch Clin Neuropsychol 18:19-32

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