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. Author manuscript; available in PMC: 2018 Oct 1.
Published in final edited form as: Trends Neurosci. 2017 Oct;40(10):592–602. doi: 10.1016/j.tins.2017.08.003

Figure 1. A pathogenic hub of Alzheimer’s centered on endosomal traffic jams.

Figure 1

As outlined in the flow diagram (upper panel) and as illustrated in the figure (lower panel), the four gene classes associated with Alzheimer’s disease are directly or indirectly linked to endosomal traffic jams. These traffic jams can occur by altering the balance of membrane traffic into the early endosomes via the endocytosis pathway (indicated by the green arrow in the figure), or more commonly by altering one of the three traffic pathways out of the early endosome (indicated by the numbered green arrows): 1. The degradation pathway, which is initiated by sorting cargo to the intraluminal vesicle (ILV). 2. The ‘recycling’ pathway to the cell surface. 3. The ‘retrograde’ pathway back to the trans-Golgi network. The four gene classes are:

Endosomal Trafficking Genes. Typified by SORL1, BIN1, CD2AP and PICALM, this class directly affects the balance of membrane trafficking in and mainly out of the early endosome, upstream to amyloid accumulation. A downstream consequence is to increase APP and/or BACE1 at the endosomal membrane, leading to intracellular accumulation of βCTF and Aβ42, or to a decrease in the intraneuronal clearance of Aβ42. As illustrated, βCTF and/or Aβ42 can feed back and worsen endosomal traffic jams, creating a vicious cycle

Cholesterol Metabolism Genes. Typified by APOE4, this class can decrease the clearance of extracellular Aβ42, which can lead to increases in intracellular Aβ42. Additionally, this class can increase endocytosis or more likely reduce endosomal recycling, with a direct effect on endosomal traffic jams.

Immune response genes. Typified by TREM2 this class can decrease the clearance of extracellular Aβ42, leading to increases in intracellular Aβ42, which in turn can contribute to endosomal traffic jams.

APP processing genes. Including mutations in APP and the presenilins, this class leads to an intracellular accumulation of Aβ42 and/or βCTF and, which can act as drivers of endosomal traffic jams.