Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid-Alzheimer's disease relationships?

Abstract

It is generally believed that cholesterol homoeostasis in the brain is both linked to and impacted by Alzheimer's disease (AD). For example, elevated levels of cholesterol in neuronal plasma and endosome membranes appear to be a pro-amyloidogenic factor. The recent observation that the C-terminal transmembrane domain (C99, also known as the beta-C-terminal fragment, or beta-CTF) of the amyloid precursor protein (APP) specifically binds cholesterol helps to tie together previously loose ends in the web of our understanding of Alzheimer's-cholesterol relationships. In particular, binding of cholesterol to C99 appears to favor the amyloidogenic pathway in cells by promoting localization of C99 in lipid rafts. In turn, the products of this pathway-amyloid-beta and the intracellular domain of the APP (AICD)-may down-regulate ApoE-mediated cholesterol uptake and cholesterol biosynthesis. If confirmed, this negative-feedback loop for membrane cholesterol levels has implications for understanding the function of the APP and for devising anti-amyloidogenic preventive strategies for AD.

Figure 1

Secondary structure and membrane topology of C99 and location of the focal point for its recognition and binding of cholesterol (red-highlighted sites), as derived from NMR studies of this protein in LMPG micelles(34).

Figure 2

NMR titration data for binding of a cholesterol analog (CHOBIMALT) to C99. A 1:1 binding model has been fit to the data, which is taken from(34) and represents the averaged values of the changes of chemical shifts for the backbone amide resonances of the residues located at the focal point for cholesterol binding to the C99 (the residues highlighted in red in Figure 1).

Figure 3

Working model for how cholesterol binding to C99/APP is related to the amyloidogenic and non-amyloidogenic pathways for processing APP and for how the amyloidogenic pathway may be linked to cellular cholesterol reduction. Given that the transmembrane product of α-secretase cleavage of APP (C83) contains the sequence motif believed to be central to cholesterol binding by C99/APP (see Figure 1), C83 probably also binds cholesterol. In this case, elevated cholesterol levels would also result in raft localization of C83, subsequent γ-secretease cleavage of which would then release AICD and an apparently harmless peptide known as p3. Whether C99/APP-cholesterol complexes in the bulk (non-raft) membranes can be cleaved by α-secretase is unclear. It is known that both full length APP and C99 can serve as substrates for α-secretase cleavage in the bulk membrane(138).