Sorting through the cell biology of Alzheimer's disease: intracellular pathways to pathogenesis

Abstract

During the first 100 years of Alzheimer's disease research, this devastating and intractable disorder has been characterized at the clinical, histological, and molecular levels. Nevertheless, many key mechanistic questions remain unanswered. Here we will emphasize the importance of the cell biology of Alzheimer's disease, reviewing the relevant literature that has expanded our mechanistic understanding, with a particular focus on pathways regulating protein sorting. Accumulated evidence indicates that sorting pathways may be uniquely vulnerable to disease pathogenesis, and recent studies have begun to reveal disease-related defects in the regulation of protein sorting.

Figure 1

Protein Sorting as a Key Mechanism in Alzheimer's Cell Biology, (A) Aβ (red bar) is liberated from its parent protein, APP (multicolor bar), in two enzymatic steps. In the first β-cleavage step, BACE (blue bar) splits full-length APP into an sAPPβ fragment (brown bar) and a C-terminal fragment (CTFβ, red/green bar). Then, in the γ-cleavage step, the γ-secretase (star) splits CTFβ into Aβ (red bar) and amyloid intracellular domain (AICD, green bar). β-cleavage is the committed step in APP processing and may be upregulated in late-onset Alzheimer's disease. (B) Both APP (red bar) and BACE (blue bar) are type-I transmembrane proteins that are sorted through multiple membranous compartments of the cell. The sorting triangle that interconnects the trans-Golgi network (TGN), cell surface, and the endosome is critically important for APP and BACE sorting. As indicated, clathrin is the coat complex that regulates transport from the cell surface and the TGN to the endosome, while the retromer is the coat complex that regulates transport from the endosome back to the TGN. A convergence of findings suggests that APP and BACE are most likely to interact within the membranes of the endosomal system, initiating the potentially amyloidogenic pathway.

Figure 2

Coat Complexes in Alzheimer's Disease, The clathrin coat (left). The clathrin coat complex transports type-I transmembrane proteins to the endosome from the TGN or from the cell surface. Each clathrin molecule is made up of three clathrin light chains (CLC) and three clathrin heavy chains (CHC). The terminal domains of CHC binds adaptor proteins (blue), which in turn bind the to-be-sorted transmembrane cargo proteins (gray bar). The adaptor proteins impose cargo and itinerary specificity. The dileucine motif found in BACE typically binds GGAs, a family of adaptor proteins engaged in clathrin-mediated transport from the TGN to the endosome. The NPXY motif found in APP binds a wide-range of adaptor proteins (as discussed in the text) engaged in clathrin-mediated transport from the cell surface to the endosome. The retromer (middle and right panels). The retromer coat complex transports type-I transmembrane proteins from the endosome to the TGN. VPS35 is the core of the retromer and binds directly to the to-be-transported type-I transmembrane protein cargo (gray bar). VPS26, VPS29, and sortin nexins (SNX) 1 or 2 assemble onto VPS35 to generate the complete functional retromer complex. Recent findings suggest that the retromer sorts APP or BACE, either by direct binding to the retromer or by indirect binding to the transmembrane adaptor protein sorLA (blue).

Figure 3

Sorting Defects in Late-Onset Alzheimer's Disease, To date, a handful of sorting molecules involved in APP and BACE transport (see Table 1) have been found to be downregulated in the brains of patients with late-onset Alzheimer's disease. Although serving multiple functions, the identified molecules all play potential roles in retromer-mediated transport (blue box, retromer; black bar, type-I transmembrane cargo protein transported from the endosome to the TGN), suggesting a model whereby endosome-to-TGN transport is a sorting itinerary particularly vulnerable to disease. When compared to normal neurons (upper panel), neurons of Alzheimer's patients (lower panel) are predicted to have diminished transport of APP and/or BACE (black bar) out of the endosome, thereby increasing the colocalization of APP and BACE in endosomes. This, in turn, could lead to excess β-cleavage and excess generation of Aβ.