Fig. 4. Model for endosomal pH regulation of synaptic Aβ production and clearance.

Endosomes are involved at multiple steps in the production and clearance of Aβ. At the cell surface (Step 1), APP can be cleaved by α- and γ-secretases (non-amyloidogenic pathway). Alternatively, APP is internalized by clathrin-dependent endocytosis at presynaptic terminals, where it undergoes amyloidogenic processing by β- and γ-secretases (Step 2). NHE6 alkalinizes the endosomal lumen, blocks trafficking of APP from the endosome to BACE1 positive vesicles, and limits Aβ production by neurons. Astrocytes clear Aβ peptides from the synaptic cleft by LRP1 receptor-mediated endocytosis (Step 3). NHE6 activity stabilizes surface expression of LRP1 and promotes Aβ clearance by astrocytes. An imbalance between Aβ production and clearance results in pathological accumulations of Aβ that could disrupt synaptic transmission and cause synapse loss (Step 4). APP amyloid precursor protein, α-Sec α-secretase, BACE1 β-secretase, GSC γ-secretase complex, BPV BACE1-positive vesicles, Aβ amyloid β, LRP1 LDL receptor-related protein 1, EE/RE early and recycling endosomes, LE/LY late endosome and lysosome, NT neurotransmitter