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A number of findings suggest that lipophilic monomeric Abeta peptides can interact with the cellular lipid membranes. These interactions can affect the membrane integrity and result in the initiation of apoptotic cell death. The secondary structure of C-terminal Abeta peptides (29-40) and the longer (29-42) variant have been investigated in solution by circular dichroism measurements. The secondary structure of lipid bound Abeta (29-40) and (29-42) peptides prepared at different lipid/peptide ratio's, was investigated by ATR-FTIR spectroscopy. Finally, the changes in secondary structure (i.e. the transition of alpha-helix to beta-sheet) of the lipid bound peptides were correlated with the induction of neurotoxic and apoptotic effects in neuronal cells. The data suggest that the C-terminal fragments of the Abeta peptide induce a significant apoptotic cell death, as demonstrated by caspase-3 measurements and DNA laddering, with consistently a stronger effect of the longer Abeta (29-42) variant. Moreover, the induction of apoptotic death induced by these peptides can be correlated with the secondary structure of the lipid bound amyloid beta peptides. Based on these observations, it is proposed that membrane bound aggregated Abeta peptides (produced locally as the result of gamma-secretase cleavage) can accumulate and aggregate in the membrane. These membrane bound beta-sheet aggregated amyloid peptides induce neuronal apoptotic cell death.

Objectives: Clinical reports have speculated on a more severe course of multiple sclerosis in patients with the apolipoprotein E (apoE) epsilon4 allele. As this could be reflected by differences in the severity of tissue damage MRI was used to obtain further support for a disease modifying effect of the apoE genotype., Methods: Brain MR scans of 83 patients (mean age 35.5 (SD 9.5 years) who participated in a cross sectional study on the distribution of genotype patterns in multiple sclerosis. The total lesion load on proton density weighted (T2-LL) and T1 weighted scans (T1-LL) obtained with conventional spin echo sequences at 1.5 T was measured. A "black hole" ratio ((T1-LL/T2-LL)x100) was also calculated. This indicates the proportion of multiple sclerosis lesions with more severe tissue damage and may reflect disease aggressiveness or quality of repair., Results: Patients with the apoE-epsilon3/epsilon4 genotype (n=19) showed a non-significantly greater T2-LL (16.0 (SD 14.0) cm(3)) than patients with the epsilon2/epsilon3 (n=11; 13.3 (9.5) cm(3)) or the epsilon3/epsilon3 genotype (n=49; 9.4 (SD 9.2) cm(3)). Both the T1-LL (2.6 (SD 3.3) v 1.6 (SD 2.4) and 1.2 (SD 3.0) cm(3); p=0.04) and the black hole ratio (14.3 SD 11.9) v 7.4 (SD 9.3) and 8.4 (SD 13.3)%; p=0.02), however, were significantly higher in epsilon3/epsilon4 patients. Similar differences were seen when comparing patients with at least one epsilon4 allele with the remainder of the group., Conclusions: These data support speculations on a modulation of multiple sclerosis severity by the apoE genotype which can be attributed to more extensive tissue destruction or less efficient repair in carriers of the epsilon4 allele.