Cholesterol Modulates Amyloid Beta-peptide’s Membrane Interactions

Abstract The causal relationship between amyloid beta-peptide (Aβ) deposition and Alzheimer’s disease (AD)-specific neuropathological lesions such as neurodegeneration and cortical atrophy is still not known. Mounting evidence points to alterations in cholesterol homeostasis occurring in AD brain that are probably linked to cerebral Aβ pathology. Interestingly, cholesterol not only modulates Aβ synthesis, but also controls interactions between Aβ and neuronal membranes that are regarded as decisive in the initiation of a neurotoxic cascade. This review focuses on the impact of cholesterol on membrane disordering effects of Aβ. Cholesterol is known to be an essential modulator of physicochemical state and functional activity in physiological membranes, and thus plays an essential role in the regulation of synaptic function and cell plasticity. IN VITRO and IN VIVO modulation of membrane cholesterol levels affect different cholesterol pools within the plasma membrane bilayer that are differentially sensitive to Aβ’s disrupting effects. Membrane acyl-chains in the hydrocarbon core are most susceptible to Aβ. In this membrane region, cholesterol attenuates the membrane disordering effects of Aβ. This cholesterol pool is modulated by methyl-beta-cyclodextrin (MβCD) treatment IN VITRO. On the other hand, statin treatment IN VIVO depletes a cholesterol pool in a membrane area, which is much less susceptible to Aβ’s membrane-disrupting effects. Our findings clearly implicate an involvement of cholesterol in brain membrane alterations occurring during AD. Disease-related changes in membrane cholesterol metabolism may be subtle and restricted to defined membrane pools since total membrane cholesterol levels are mainly unchanged in AD brain. Thus, elucidation of the structure and function of different cholesterol pools is necessary in understanding the coherence between cholesterol and AD.