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Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer’s disease

Kim, S, Sato, Y, Mohan, P S, Peterhoff, C, Pensalfini, A, Rigoglioso, A, Jiang, Y, Nixon, R A·2016·Molecular Psychiatry
DOI 10.1038/mp.2015.97PMC PMC4721948
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Abstract

β-Amyloid precursor protein (APP) and its cleaved products are strongly implicated in Alzheimer’s disease (AD). Endosomes are highly active APP processing sites, and endosome anomalies associated with upregulated expression of early endosomal regulator, rab5, are the earliest known disease-specific neuronal response in AD. Here, we show that the rab5 effector APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif) mediates rab5 overactivation in Down syndrome (DS) and AD, which is caused by elevated levels of the β-cleaved carboxy-terminal fragment of APP (βCTF). βCTF recruits APPL1 to rab5 endosomes, where it stabilizes active GTP-rab5, leading to pathologically accelerated endocytosis, endosome swelling and selectively impaired axonal transport of rab5 endosomes. In DS fibroblasts, APPL1 knockdown corrects these endosomal anomalies. βCTF levels are also elevated in AD brain, which is accompanied by abnormally high recruitment of APPL1 to rab5 endosomes as seen in DS fibroblasts. These studies indicate that persistent rab5 overactivation through βCTF–APPL1 interactions constitutes a novel APP-dependent pathogenic pathway in AD.

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Crossref · 10.1038/mp.2015.97

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  • VPS35 dysfunction leads to APP accumulation in early endosomes.

    “VPS35 dysfunction leads to APP accumulation in early endosomes, increased Aβ production and exosomal release, and enlarged axonal endosomes [9, 16, 20].”

    From Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer’s disease mouse model (2025) · cites this paper as [20]

    The Results describe APP-βCTF/APPL1-mediated endosome enlargement and transport defects, not VPS35 dysfunction causing APP to accumulate in early endosomes. A search for VPS35 and retromer found a VPS35 study in the References, but no passage in this paper's text stating the claimed mechanism. No page numbers were available in our copy. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • VPS35 dysfunction leads to enlarged axonal endosomes.

    “VPS35 dysfunction leads to APP accumulation in early endosomes, increased Aβ production and exosomal release, and enlarged axonal endosomes [9, 16, 20].”

    From Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer’s disease mouse model (2025) · cites this paper as [20]

    The Results section reports enlarged neuronal endosomes after APP and rab5 overexpression, and the Discussion links enlargement to rab5-mediated endocytosis and fusion. Neither passage attributes enlarged axonal endosomes to VPS35 dysfunction. A search for VPS35 found a reference to a VPS35 paper but no passage in this paper establishing the claimed link; page numbers were unavailable in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • VPS35 dysfunction leads to increased Aβ production and exosomal release.

    “VPS35 dysfunction leads to APP accumulation in early endosomes, increased Aβ production and exosomal release, and enlarged axonal endosomes [9, 16, 20].”

    From Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer’s disease mouse model (2025) · cites this paper as [20]

    The Discussion identifies lowered VPS35 as a possible contributor to rab5 endosome dysfunction, but does not say it increases Aβ production or exosomal release. Searches for VPS35 with Aβ production and exosomal release found no passage in our copy establishing either claimed effect. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

  • C99 accumulates in the brains of AD patients.

    “C99 accumulates in the brains of AD patients (Pera et al., 2013; Kim et al., 2016)”

    From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Kim et al., 2016

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Metadata

Authors
Kim, S., Sato, Y., Mohan, P. S., Peterhoff, C., Pensalfini, A., Rigoglioso, A., Jiang, Y., & Nixon, R. A.
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2015-07-21
Volume
21
Issue
5
Pages
707-716
ISSN
  • 1359-4184
  • 1476-5578
DOI
10.1038/mp.2015.97
PMC
PMC4721948
Cited by
212
References
7
Language
en
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