Dysregulation of intracellular trafficking and endosomal sorting in Alzheimer's disease: controversies and unanswered questions

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of amyloid plaques in the brain consisting of an aggregated form of amyloid β-peptide (Aβ) derived from sequential amyloidogenic processing of the amyloid precursor protein (APP) by membrane-bound proteases β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase. The initial processing of APP by BACE1 is re-gulated by intracellular sorting events of the enzyme, which is a prime target for therapeutic intervention. GWAS (genome-wide sequencing studies) have identified several AD-susceptibility genes that are associated with the regulation of membrane trafficking, and substantial evidence now indicates that AD is likely to arise from defective membrane trafficking in either or both of the secretory and endocytic pathways. Considerable progress has been made in defining the intracellular trafficking pathways of BACE1 and APP and the sorting signals of these membrane proteins that define their itineraries. In this review we highlight recent advances in understanding the regulation of the intracellular sorting of BACE1 and APP, discuss how dysregulation of these trafficking events may lead to enhanced generation of the neurotoxic Aβ products in AD and highlight the unresolved questions in the field.

MT5-MMP Promotes Alzheimer’s Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro

“…Extensive experimental evidence supports the view that APP not cleaved by γ-secretase at the plasma membrane is rapidly internalized and processed into C99 by BACE-1 in endosomes. The latter provide the acidic microenvironment for optimal BACE-1 function (Haass et al, 2012; Toh and Gleeson, 2016). In these conditions, it is likely that 6E10 + immunostaining detected in early endosomes mainly reveals the content of C99 and/or Aβ, as previously suggested (Kaether et al, 2006b).…”

“…The finding that Aβ40 levels are also upregulated in these organelles supports the idea that both C99 and Aβ coexist in the same compartment, and implicitly, the same holds true for β- and γ-secretase. The precise subcellular localization of β- and γ-secretases is still an open debate, but growing evidence indicates that both may be present in early endosomes (Rajendran and Annaert, 2012; Toh and Gleeson, 2016). Importantly, our data strongly suggest that after internalization MT5-MMP and APP converge towards early endosomes, in agreement with data reported for APP in various cell types (Rajendran and Annaert, 2012; Toh and Gleeson, 2016) and with one report on MT5-MMP in native HEK cells (Wang et al, 2004).…”

“…The precise subcellular localization of β- and γ-secretases is still an open debate, but growing evidence indicates that both may be present in early endosomes (Rajendran and Annaert, 2012; Toh and Gleeson, 2016). Importantly, our data strongly suggest that after internalization MT5-MMP and APP converge towards early endosomes, in agreement with data reported for APP in various cell types (Rajendran and Annaert, 2012; Toh and Gleeson, 2016) and with one report on MT5-MMP in native HEK cells (Wang et al, 2004). Thus, early endosomes could be a privileged subcellular locus of the pro-amyloidogenic interactions between MT5-MMP and APP we described earlier (Baranger et al, 2016b).…”

Analysis of novel endosome-to-Golgi retrieval genes reveals a role for PLD3 in regulating endosomal protein sorting and amyloid precursor protein processing

“…The trafficking and localisation of APP within the post-Golgi endocytic system plays an important role in regulating the exposure of APP to the secretases that mediate its cleavage to form Aβ peptides [2, 3]. Most evidence now supports a model whereby the cleavage of APP to generate Aβ occurs in an endocytic compartment where β-secretase (BACE) is predominately localised [4].…”

Honokiol Attenuates Oligomeric Amyloid β1-42-Induced Alzheimer’s Disease in Mice Through Attenuating Mitochondrial Apoptosis and Inhibiting the Nuclear Factor Kappa-B Signaling Pathway

“…The Aβ is released into the extracellular space and self-aggregates to form oligomers that toxic to neuronal cells. In the non-amyloidogenic pathway, APP was cleaved by α-secretase within the Aβ sequence to produce a soluble secretory amyloid precursor protein (sAPPα) [2, 3]. Thus, factors that trigged overwhelming amyloidogenic pathway and inhibited non-amyloidogenic pathway will result in overproduction of Aβ.…”