Mechanisms of disease: new therapeutic strategies for Alzheimer's disease--targeting APP processing in lipid rafts

Abstract

Alzheimer's disease (AD) is the most common cause of age-related dementia. Pathologically, AD is characterized by the deposition in the brain of amyloid-beta peptides derived from proteolysis of amyloid precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) and gamma-secretase. A growing body of evidence implicates cholesterol and cholesterol-rich membrane microdomains in amyloidogenic processing of APP. Here, we review recent findings regarding the association of BACE1, gamma-secretase and APP in lipid rafts, and discuss potential therapeutic strategies for AD that are based on knowledge gleaned from the membrane environment that fosters APP processing.

Figure 1

Schematic diagram of intracellular amyloid precursor protein (APP) trafficking in a model cell. Nascent APP matures through the constitutive secretory pathway (1). Once APP reaches the cell surface, it is rapidly internalized and subsequently trafficked through endocytic (2) and recycling compartments (3) back to the cell surface, or is degraded in lysosomes. Nonamyloidogenic processing occurs mainly at the cell surface, where α-secretase activity is abundant. Amyloidogenic processing involves transit through the endocytic organelles, where APP encounters β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase. Abbreviations: EE, early endosome; RE, recycling endosome.

Figure 2

Distribution of amyloid precursor protein (APP) and secretases in membrane microdomains. (A) The brain of a 12-month-old mouse was homogenized and solubilized in a buffer containing 0.5% Lubrol WX at 4°C for 30 min. The lysates were then subjected to flotation sucrose density gradient centrifugation to separate cholesterol-rich detergent-insoluble membranes (enriched in lipid raft markers) from detergent-soluble proteins. An equal volume of each fraction was analyzed by Western blotting with antibodies against the APP C-terminus,β-site APP-cleaving enzyme 1 (BACE1), presenilin 1 (PS1) and nicastrin. (B) A model depicting compartmentalization of APP C-terminal fragments and secretases in lipid rafts. Full-length APP (APP FL) is predominantly localized in non-raft regions of membranes, whereas APP C-terminal fragments are highly abundant in lipid rafts. BACE1 appears to be distributed evenly between raft and non-raft domains, whereas γ-secretase preferentially associates with lipid rafts. α-secretases are excluded from lipid rafts, and are not shown here for the sake of clarity. Abbreviations: APP CTF, amyloid precursor protein C-terminal fragments; APP FL, full-length amyloid precursor protein; BACE1, β-site APP-cleaving enzyme 1; PS1 NTF, presenilin 1 N-terminal fragments.

Figure 3

Models of amyloid precursor protein (APP) processing. (A) Model 1 is deduced from raft and non-raft distribution of BACE1 and paucity of full-length APP (APP FL) in membrane microdomains. BACE1 cleaves a subset of APP FL in non-raft regions. The resulting APP β-C-terminal fragment becomes associated with lipid rafts and is processed by raft-associatedγ-secretase. (B) Model 2 depicts an alternative interpretation of the data in Figure 1A. A subset of APP FL becomes associated with lipid rafts, and is sequentially processed by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase. The models differ with respect to the microdomain localization of BACE1 cleavage, which has not been fully resolved on the basis of cholesterol depletion studies.,, Abbreviations: APP, amyloid precursor protein; Aβ, amyloid-β; APPsβ, BACE1-generated amyloid precursor protein ectodomain; BACE1, β-site APP-cleaving enzyme 1; β-CTF; amyloid precursor protein β-C-terminal fragment.