Modulation of beta-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family - PubMed (original) (raw)

Modulation of beta-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family

Judy A Cam et al. Mol Neurodegener. 2006.

Abstract

Amyloid-beta peptide (Abeta) accumulation in the brain is an early, toxic event in the pathogenesis of Alzheimer's disease (AD). Abeta is produced by proteolytic processing of a transmembrane protein, beta-amyloid precursor protein (APP), by beta- and gamma-secretases. Mounting evidence has demonstrated that alterations in APP cellular trafficking and localization directly impact its processing to Abeta. Recent studies have shown that members of the low-density lipoprotein receptor family, including LRP, LRP1B, SorLA/LR11, and apolipoprotein E (apoE) receptor 2, interact with APP and regulate its endocytic trafficking. Another common feature of these receptors is their ability to bind apoE, which exists in three isoforms in humans and the presence of the epsilon4 allele represents a genetic risk factor for AD. In this review, we summarize the current understanding of the function of these apoE receptors with a focus on their role in APP trafficking and processing. Knowledge of the interactions between these distinct low-density lipoprotein receptor family members and APP may ultimately influence future therapies for AD.

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Figures

Figure 1

Figure 1

Schematic representation of APP processing. APP is a type I transmembrane protein that can undergo two separate proteolytic pathways. In the non-amyloidogenic pathway, APP is processed by an α-secretase that clips within the Aβ region (thus precluding its formation), resulting in the release of a soluble ~110–120 kDa N-terminal APP fragment (sAPPα). This pathway also releases a CTF that is 83 amino acids in length (C83). C83 can also be cleaved by a γ-secretase to release a small, non-toxic 3 kDa fragment known as p3 and a γCTF known as APP intracellular domain (AICD). In the amyloidogenic pathway, APP is cleaved first by β-secretase releasing a sAPPβ fragment and leaving a 99 amino acid CTF attached to the membrane (C99). C99 is subsequently cleaved by a γ-secretase, within its intramembrane region to release the Aβ peptide and AICD. SP, Signal Peptide; KPI, Kunitz-type Proteinase Inhibitor domain.

Figure 2

Figure 2

Schematic representation of members of the LDLR family. Members of the LDLR family have diverse functions from cholesterol metabolism, Reelin and Wnt signalling, to intracellular transport. Despite multiple functions, they share common structural motifs, including ligand-binding repeats, epidermal growth factor (EGF) repeats, YWTD spacer domains, a single transmembrane domain and a short cytoplasmic domain containing conserved endocytic motifs. FN, fibronectin.

Figure 3

Figure 3

Model of APP processing pathways mediated by LDL receptor family members. LRP endocytosis enhances APP endocytosis and processing to Aβ. Due to its slow rate of endocytosis LRP1B retains APP at the cell surface and decreases its processing to Aβ. ApoER2 enhances interactions between APP and F-spondin at the cell surface and also decreases its processing to Aβ. SorLA/LR11 may shuttle APP to the Golgi and prevent its processing by β-secretase in the early endosome, thus decreasing processing to Aβ.

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