Modulation by age and gender of risk for Alzheimer's disease and vascular dementia associated with the apolipoprotein E-epsilon4 allele in Latin Americans: findings from the Maracaibo Aging Study.

An ongoing longitudinal study in Maracaibo, Venezuela, examined the interaction between apolipoprotein E (APOE) genotypes and Alzheimer's disease (AD) and vascular dementia (VD), evaluating age and gender as potential modifiers of risk. Overall, carriers of at least one epsilon4 allele were at higher risk for AD, not for VD; however, the risk was significant only for subjects older than 65, and it increased 10-fold in subjects older than 85. The risk of AD conferred by APOE-epsilon4, adjusted for age and stratified by gender, was significant only for women. No association was found between the epsilon-2 allele and AD or VD. The results support the notions that APOE-epsilon4 is relevant for late-onset, not early onset AD, and that age and gender act as modulators of this association.

Intercellular interactions in PC12 cells overexpressing beta/A4 amyloid.

The amyloid precursor protein (APP) is an integral membrane component of eukaryotic cells. A variety of research approaches have addressed the contribution of the beta amyloid peptide region of the APP to neuritic plaque structure and formation in the Alzheimer disease brain as well as the relationship between beta amyloid accumulation and the occurrence of dementia. However, there is limited information available concerning the cellular consequences of amyloid deposition. The present studies were undertaken to investigate the relationship between beta amyloid and intercellular junctions. Transfected PC12 cell lines, that overexpress the beta amyloid peptide, exhibit structural and functional alterations at the cell surface and tend to form aggregates more readily than normal control cells. Intermediate junctions were the most common intercellular interactions of both normal and transfected cells. However, the control and transfected cells differed since areas of continuous and extensive junctions were readily seen in transfected cells and infrequently seen in control cells. The data suggest that excess accumulation of beta amyloid is associated with the junctional apparatus and may be related to increased intercellular adhesion.

Membrane surface ruffling in cells that over-express Alzheimer amyloid beta/A4 C-terminal peptide.

Deposition of beta/A4 amyloid in brain is a defining characteristic of Alzheimer disease (AD); however, the extent to which amyloid deposits may interfere with normal cellular processes is incompletely understood. We examined this issue by means of PC12 cells. After transfection with DNA coding for 97 amino acids of the beta/A4 C-terminal region of the amyloid precursor protein, beta/A4 antigen was visible at the cell membrane. We report that normal unstimulated PC12 cells exhibit ruffling activity at the cell surface when plated on a plastic substrate. Relative to control cells, however, those that over-expressed the beta/A4 C-terminal peptide had significantly higher levels of ruffling activity, suggesting a structural and/or functional membrane modification. Similar cellular alterations, if present, in Alzheimer brain cells, may indicate disturbances in membrane-associated functions, including intercellular communication.

Cell surface extensions associated with overexpression of Alzheimer beta/A4 amyloid.

Deposition of beta/A4 amyloid in Alzheimer disease (AD) brain parenchyma and vasculature occurs by mechanisms that are currently undefined. Similarly the potential consequences of amyloid accumulation for disrupting cellular integrity have not been addressed in detail. To investigate the possible significance of amyloid deposits for cellular viability, PC12 cells were permanently transfected with DNA coding for the beta/A4-C terminal region of the amyloid precursor protein. The DNA represented 97 amino acids of the amyloid precursor protein of which 40 amino acids were derived from the beta/A4 region. Transfected clonal cell lines and controls were examined at both the light and electron microscopic levels for morphological abnormalities. beta/A4 amyloid accumulated in the cell membrane where the peptide was located at cellular processes resembling blebs and microvilli. These specialized structures at the cell surface were over-abundant in transfected cells that overexpressed the beta/A4 peptide but not in controls. Membranous processes may be involved in the delivery of the beta/A4 peptide to the external surface of the cell of origin and release into the extracellular space. Similar surface features of cells in the AD brain, should they occur, may indicate a role for membrane-associated processes in the pathophysiology of the disorder.