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Diverse Interactions of Sterols with Amyloid Precursor Protein Transmembrane Domain Can Shift Distribution Between Alternative Amyloid-β Production Cascades in Manner Dependent on Local Lipid Environment
Alzheimer’s disease (AD) pathogenesis is correlated with the membrane content
of various lipid species, including cholesterol, whose interactions with amyloid precursor
protein (APP) have been extensively explored. Amyloid-β peptides triggering AD are
products of APP cleavage by secretases, which differ depending on the APP and secretase location
relative to ordered or disordered membrane microdomains. We used high-resolution
NMR to probe the interactions of the cholesterol analog with APP transmembrane domain
in two membrane-mimicking systems resembling ordered or perturbed lipid environments
(bicelles/micelles). In bicelles, spin-labeled sterol interacted with the peptide near the
amphiphilic juxtamembrane region and N-terminal part of APP transmembrane helix,
as described earlier for cholesterol. Upon transition into micellar environment, another
interaction site appeared where sterol polar head was buried in the hydrophobic core near
the hinge region. In MD simulations, sterol moved between three interaction sites, sliding
along the polar groove formed by glycine residues composing the dimerization interfaces
and flexible hinge of the APP transmembrane domain. Because the lipid environment
modulates interactions, the role of lipids in the AD pathogenesis is defined by the state of
the entire lipid subsystem rather than the effects of individual lipid species. Cholesterol can
interplay with other lipids (polyunsaturated, gangliosides, etc.), determining the outcome
of amyloid-β production cascades.