Increased platelet membrane fluidity (PMF), as measured by a decrease in the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPh) in labeled membranes, identifies a subgroup of patients with Alzheimer's disease (AD) who have distinct clinical features. This phenotype appears to be a stable, familial trait that is vertically transmitted in families of patients with Alzheimer's disease. Segregation analysis of data from these families indicates that increased PMF results from the inheritance of a single major locus that controls at least 80% of the variance in this membrane phenotype. Thus, the PMF locus appears to be an important and common genetic source of clinical heterogeneity in Alzheimer's disease. At the cellular level, evidence from ultrastructural and biochemical studies suggests that increased PMF results from an accumulation of abnormal internal membranes resembling smooth endoplasmic reticulum that may be functionally abnormal. During the requested award period, we propose to prospectively evaluate increased PMF as a risk factor for AD, to further define the cellular and molecular basis for increased PMF, and to use this information to direct hypothesis-driven studies of post-mortem brain tissue aimed at elucidating the pathophysiology of AD.
Our specific aims are to: 1. Determine whether increased PMF predicts the incidence of primary dementia in a high-risk cohort of 330 first-degree relatives of patients with AD who were cognitively intact at the time of entry into this ongoing longitudinal study. As part of this study, transformed cell lines will be established to facilitate future studies of putative genetic risk factors for AD. 2. Determine whether the PMF locus is located on the long arm chromosome 21, where several genes related to the biology of AD have been previously localized, or near a region of chromosome 19 reported to confer vulnerability to AD. 3. Determine the frequency and distribution of point mutations across the transmembrane region of the APP gene in patients with confirmed AD and patients who did not have AD at the time of death. 4. Determine directly whether increased PMF results form an accumulation of internal membranes, a selective increase in the fluidity of internal platelet membranes, or both, using isolated preparations of internal and external platelet membranes. If, as suggested by our preliminary studies, both alterations are observed, the membrane compositional changes responsible for the increased fluidity of the internal membranes will also be investigated. 5. Determine the distribution of the soluble and membrane-bound forms of b-amyloid precursor protein (APP) in platelets, and investigate whether the processing or distribution of this glycosylated membrane protein is altered in AD patients with increased PMF. 6. Examine the relationship of antemortem determinations of PMF to the densities of senile plaques and neurofibrillary tangles in the brains of patients who died with confirmed AD.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
3P41RR006009-09
Application #
6282500
Study Section
Project Start
1998-08-01
Project End
1999-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Mellon Pitts Corporation (Mpc Corp)
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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