Editors' ChoiceAlzheimer’s Disease

Blaming an unusual suspect for endosomal traffic jams in Alzheimer’s disease

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Science Translational Medicine  21 Aug 2019:
Vol. 11, Issue 506, eaaz0730
DOI: 10.1126/scitranslmed.aaz0730


Accumulation of β–C-terminal fragments, not β-amyloid, drives early endosomal alterations in familial Alzheimer’s disease human neurons.

Rare forms of familial Alzheimer’s disease (fAD) taught us that amyloid precursor protein (APP) cleavage is central to its pathogenesis; identifying other phenotypes shared by these familial mutations may help us to further understand other forms of the disease. Following this rationale, Kwart and colleagues analyzed the transcriptome and translatome of cortical neurons derived from induced pluripotent stem cells edited to harbor two widely studied amyloid precursor protein (APP) and Presenilin 1 (PSEN1) mutations, alone or in combination.

Amongst the differentially expressed genes and translated mRNAs, they focused on those associated with endosomes. Endosomal trafficking defects have previously been proposed to occur early in AD, and some AD-associated genes such as Apolipoprotein E (APOE) play a role in this form of intracellular transport. To validate these findings, the authors expanded their panel of mutant lines to four APP and three PSEN1 additional mutations, and they looked for endosomal defects using enlargement of early endosomes as a proxy. When in homozygosity, all mutations led to the accumulation of large vesicles. A comprehensive analysis of APP metabolites produced by each of the mutant lines revealed that all secreted longer, more pathogenic, variants of β-amyloid (Aβ), and they also accumulated APP cleavage byproducts known as β–C-terminal fragments (β-CTF). Via pharmacological manipulation of neurons, the authors demonstrated that reducing the accumulation of β-CTFs specifically, rather than lowering longer Aβ fragments, reversed the endosomal enlargements.

Whether endosomal trafficking defects in AD are caused by Aβ or β-CTF is an ongoing debate, but the usage in this study of human neurons expressing diverse fAD mutations at endogenous protein levels makes a strong case in favor of the latter. However, it will be important to test in this system if endosomal alterations link to neuronal death, and whether preventing accumulation of β-CTFs can arrest degeneration. Regardless, future studies in the field should move beyond the amyloid hypothesis to tackle the possible pathologic effects of other APP metabolites and consider targeting those therapeutically, given the recent failures of Aβ immunotherapies.

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