Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease

Abstract

Abnormalities of the endosomal-lysosomal network (ELN) are a signature feature of Alzheimer's disease (AD). These include the earliest known cytopathology that is specific to AD and that affects endosomes and induces the progressive failure of lysosomes, each of which are directly linked by distinct mechanisms to neurodegeneration. The origins of ELN dysfunction and β-amyloidogenesis closely overlap, which reflects their common genetic basis, the established early involvement of endosomes and lysosomes in amyloid precursor protein (APP) processing and clearance, and the pathologic effect of certain APP metabolites on ELN functions. Genes that promote β-amyloidogenesis in AD (APP, PSEN1/2, and APOE4) have primary effects on ELN function. The importance of primary ELN dysfunction to pathogenesis is underscored by the mutations in more than 35 ELN-related genes that, thus far, are known to cause familial neurodegenerative diseases even though different pathogenic proteins may be involved. In this article, I discuss growing evidence that implicates AD gene-driven ELN disruptions as not only the antecedent pathobiology that underlies β-amyloidogenesis but also as the essential partner with APP and its metabolites that drive the development of AD, including tauopathy, synaptic dysfunction, and neurodegeneration. The striking amelioration of diverse deficits in animal AD models by remediating ELN dysfunction further supports a need to integrate APP and ELN relationships, including the role of amyloid-β, into a broader conceptual framework of how AD arises, progresses, and may be effectively therapeutically targeted.-Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease.

Keywords: Down Syndrome; apoliprotein E; autophagy; cholinergic neurodegeneration; presenilin.

Figure 1.

The ELN network. The term, network, emphasizes that lysosomes degrade cargoes that are delivered by both endocytic and autophagic routes and that, in neurons especially, these pathways merge when endosomes frequently fuse with autophagosomes before lysosome fusion. Network also refers to the extensive crosstalk between endocytic and autophagic pathways in terms of regulatory mechanisms and involvement of endocytic pathway components (e.g., rab5, rab9, rab7, endosomal sorting complex required for transport components, etc.) in the formation, function, and maturation of autophagosomes. Endocytic pathway to lysosomes: endocytosis, reviewed in detail elsewhere (–5), involves internalization of extracellular material and plasma membrane via clathrin-dependent and -independent routes and additional cargoes from the Golgi, which are delivered to an early endosome with both signaling and cargo-sorting properties (inset). Sorting of cargo includes recycling of proteins and lipids to the plasma membrane in fast- or slow-recycling endosomes that are regulated, in part, by Rab4 or Rab11 and the retromer, respectively (11, 13). The retromer also traffics vesicle-bound constituents, notably APP, back and forth from the Golgi. Additional trafficking signals commit other early endosome cargoes to downstream sorting or degradation via late endosomes (LEs) and lysosomes. During maturation to LE (6, 30), an LE/multivesicular body (MVB) is created by the inward budding of the surface membrane to form a collection of internal vesicles (102). This process reduces endosome volume and provides access of the internalized membranes to hydrolases while also creating a population of exosomes that can be released extracellularly rather than degraded internally. LEs/MVBs fuse with lysosomes (endolysosomes) or, in neurons, more commonly fuse with autophagosomes to form amphisomes before fusing with lysosomes (autolysosomes). Autophagic routes to the lysosome include macroautophagy: structures/cytoplasm targeted for degradation are sequestered via a phagophore that forms a double membrane-limited autophagosome that fuses with lysosomes; chaperone-mediated autophagy, which directs select proteins that carry the pentapeptide KFERQ-like sequence directly into lysosomes via chaperones (e.g., Hsc70) and translocation machinery (e.g., lysosome-associated membrane protein-2a); and microautophagy (not shown) involving bulk or chaperone-facilitated internalization of cytoplasmic substrates into an endolysosomal compartment for degradation.

Figure 2.

Genetics of AD implicate both APP and ELN in AD pathogenesis. AD-related causative and risk factor genes and aging disrupt ELN function directly and promote β-amyloidogenesis by altering APP cleavage and turnover directly or by modifying APP metabolism via ELN dysfunction. APP and ELN biology are intertwined via the biologic actions of genes that are responsible for AD risk. The critical roles of βCTF (C99) and Aβ are indicated and discussed further in the text. Of note, the Icelandic APP mutation that lowers risk for AD is believed to act by reducing BACE1 cleavage of APP (216), thus reducing levels of APP–βCTF and Aβ. EE, early endosome; LE, late endosome.

Figure 3.

APP–βCTF mediates pathologic activation of rab5 on endosomes in AD, which leads to compromise of cholinergic neurons. A) Recruited APPL1 binds via its phosphotyrosine binding (PTB) domain to the YENPT domain of APP–βCTF. APPL1 dimerization via BAR domains facilitates vesicle curvature and binding of GTP-rab5 via the PH domain stabilizes rab5 in this activated state on endosomes. B) Rab5 hyperactivation slows endosome transport and diminishes TrkA signaling, which leads to the loss of trophic support for cholinergic neurons.