Abstract
The interaction of A beta peptides with the lipid matrix of neuronal cell membranes plays an important role in the pathogenesis of Alzheimer's disease. By using EPR and CD spectroscopy, we found that in the presence of Cu(2+) or Zn(2+), pH, cholesterol, and the length of the peptide chain influenced the interaction of these peptides with lipid bilayers. In the presence of Zn(2+), A beta 40 and A beta 42 both inserted into the bilayer over the pH range 5.5-7.5, as did A beta 42 in the presence of Cu(2+). However, A beta 40 only penetrated the lipid bilayer in the presence of Cu(2+) at pH 5.5-6.5; at higher pH there was a change in the Cu(2+) coordination sphere that inhibited membrane insertion. In the absence of the metals, insertion of both peptides only occurred at pH < 5.5. Raising cholesterol to 0.2 mol fraction of the total lipid inhibited insertion of both peptides under all conditions investigated. Membrane insertion was accompanied by the formation of alpha-helical structures. The nature of these structures was the same irrespective of the conditions used, indicating a single low energy structure for A beta in membranes. Peptides that did not insert into the membrane formed beta-sheet structures on the surface of the lipid.
Highlights
Alzheimer’s disease (AD)1 is a neurodegenerative disorder affecting the memory and cognitive functions of the brain
The common change observed in cell membrane permeability is an increased intracellular calcium level [5, 6] that could occur either indirectly through A modulating an existing Ca2ϩ channel or directly through cation-selective channels formed by A
Effect of pH and Peptide Length on Interaction of A Peptides with LUV—Fig. 1 shows the EPR spectra recorded at 305 K of 16NPS in POPS/POPC (1/1) LUV and the same LUV containing amyloid -peptide (A)42 before and after the addition of Cu2ϩ (0.3/1 M peptide) at pH 7.5, 7.0, 6.5, 6.0, and 5.5
Summary
Materials and Methods—Peptides were obtained from AusPep (Melbourne, Australia) and from the W. As a check on the validity of these procedures as applied to our system where an MRLC was observed, the lipid spin label spectra were simulated using the modified Bloch equations as described by Davoust and Devaux [21]. Their model I was used in the simulations where the unique director orientation in the fluid component, corresponding to the nitroxide axes being aligned along the membrane normal in the MRLC, was assumed to be preserved on exchange. CD Spectroscopy—CD spectra of peptides in the LUV were obtained using a CD spectropolarimeter model 62DS (AVIV, Lakewood, NJ) as described previously [10]
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