Trafficking and proteolytic processing of APP

Abstract

Accumulations of insoluble deposits of amyloid β-peptide are major pathological hallmarks of Alzheimer disease. Amyloid β-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the β-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. β- and γ-secretase liberate by sequential cleavage the neurotoxic amyloid β-peptide, whereas α-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid β-peptide generation and therefore disease onset and progression.

Figure 1.

Proteolytic processing of APP within the anti-amyloidogenic (left) and amyloidogenic (right) pathways.

Figure 2.

Biological function of BACE1 in myelination. (A) A BACE1 knockout in mice results in a hypomyelination phenotype within the peripheral nervous system. Cross-sections through the sciatic nerve of wild-type mice and BACE knockout mice are shown. (B) Proteolytic processing of NRG1 type III. NRG1 type III is cleaved by BACE1. This processing step leads to the exposure of EGF-containing domain and facilitates signaling via ErbB4 in Schwann cells.

Figure 3.

Sequential processing of APP by γ-secretase.

Figure 4.

Intracellular trafficking of APP. Nascent APP molecules (black bars) mature through the constitutive secretory pathway (1). Once APP reaches the cell surface, it is rapidly internalized (2) and subsequently trafficked through endocytic and recycling organelles to the TGN or the cell surface (3). A small fraction is also degraded in the lysosome. Nonamyloidogenic processing mainly occurs at the cell surface where α-secretases are present. Amyloidogenic processing involves transit through the endocytic organelles where APP encounters β- and γ-secretases.

Figure 5.

Polarized sorting of APP in MDCK cells. (A) Two independent basolateral sorting pathways for αAPPs via a NH₄Cl-sensitive compartment (blue) and full-length APP (red). (B) Inhibition of vesicular acidification by NH₄Cl leads to random secretion of αAPPs whereas full-length APP is still sorted to the basolateral membrane. (C) APP lacking a cytoplasmic signal for basolateral sorting (ΔC APP) undergoes random surface transport.

Figure 6.

Polarized sorting APP, its processing products, and its secretases.

Figure 7.

Neuronal APP transport and processing. (A) Post-Golgi sorting of APP. APP as well as APPΔC is transported by fast axonal transport along the axon and by as yet uncharacterized transport into dendrites. Transport to and fusion with the plasma membrane in the neuronal soma is likely, but has not been characterized. (B) Transport and sorting of APP and secretases. APP and α-secretase are transported in axonal carriers that do not contain β- or γ-secretase. Whether β- and γ-secretase are transported together is not known. Colocalization of APP and secretases in dendritic transport vesicles has not been studied. (C) Release of Aβ occurs at presynaptic sites, but whether it is also released from axon shafts is unknown. Aβ is released from dendrites, but the exact location has not been determined. Where APP fuses with the axonal and dendritic plasma membrane and where processing by secretases occurs remains elusive.