Figure 6.

NGF retrograde signaling and involvement of APPL1 in healthy neurons and after a rise in neuronal APPL1 levels related to Alzheimer's disease in APPL1 overexpressing neurons. Schematic diagram depicts (A) the endocytosis of APP, NGF, and its receptor TrkA into a rab5 early endosome. TrkB mediation of BDNF signaling by APPL1 (data not shown) is considered to follow a similar sequence. B, Normal NGF signaling is facilitated by recruitment of APPL1, a direct TrkA ligand and adaptor for other signaling molecules mediating retrograde transport of a maturing endosome carrying the NGF signal to the nucleus to activate a neurotrophic transcriptional program supporting functioning of ChAT neurons and other NGF targets. In AD (not shown; see main text), abnormally elevated APP-βCTF levels arising via multiple possible mechanisms raise levels of the activated form of rab5 (rab5-GTP) on endosomal membranes, in part by recruiting more APPL1 to the endosome via the phosphotyrosine binding (PTB) domain of APPL1 (Kim et al., 2016). APPL1's greater affinity for rab5-GTP prolongs association of this activated form on the endosome, thus promoting a pathogenic rab5 hyperactivation leading to increased endocytosis, early endosomal fusion, and endosome enlargement, as depicted in C. C, Moderately elevating APPL1 selectively in neurons of Thy1-APPL1 mice phenocopies mouse models of APP-βCTF elevation or rab5 overexpression with respect to rab5 hyperactivation, abnormal endosome enlargement, stasis of endosome transport, synaptic plasticity deficits, and basal forebrain cholinergic neurodegeneration. These pathological effects, as observed in AD brain, also reflect impaired NGF/TrkA signaling and decreased expression of genes for neuronal survival, growth and differentiation (Niewiadomska et al., 2011; Xu et al., 2018). Further information is provided in the text and in more detail in reviews (Nixon, 2017; Nixon and Rubinsztein, 2024).