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

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 mediates rab5 over-activation 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 Alzheimer brain, which is accompanied by abnormally high recruitment of APPL1 to rab5 endosomes as seen in DS fibroblasts. These studies indicate that persistent rab5 over-activation through βCTF-APPL1 interactions constitutes a novel APP-dependent pathogenic pathway in AD.

Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons

“…Endosomal abnormalities could result from accumulation of Aβ or CTF-β [32,64], Photographs illustrate APP exosomes localized on dendritic spine necks (empty arrowhead), dendritic spine heads (white arrowheads), or dendritic shaft (white arrow). Bar 10 μm.…”

Expression of APPL1 Is Correlated with Clinicopathologic Characteristics and Poor prognosis in Patients with Gastric Cancer

“…The activated oncogenes can induce angiogenesis with consequent infiltration and metastasis 32 and can inhibit apoptosis by inhibiting TP53 33 . Kim et al found that RAB5A (formerly RAB5) acting through appl1 mediation induced dysfunction of endosomes 34 . Recent studies showed that activation of RAB5A was a significant event in maintaining the dynamics of focal cellular adhesions, influencing not only cell migration, but also tumour cell invasion 35 .…”

Amyloid-β and lysozyme proteotoxicity in Drosophila : Beneficial effects of lysozyme and serum amyloid P component in models of Alzheimer’s disease and lysozyme amyloidosis

“…C99 is able to bind directly to human adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1, APPL1, which in turn recruits and pathologically activates Rab5, leading to cholinergic neurodegeneration in Down syndrome patient cells, i.e. cells carrying one extra copy of AβPP and thus expressing higher levels of the Aβ peptide (Kim et al, 2016). Furthermore, the amount of the C99 fragment has been shown to be higher in AD brains even though normal levels of AβPP were detected, and the same over-activation of Rab5 could also be observed in AD brains (Kim et al, 2016).…”

“…cells carrying one extra copy of AβPP and thus expressing higher levels of the Aβ peptide (Kim et al, 2016). Furthermore, the amount of the C99 fragment has been shown to be higher in AD brains even though normal levels of AβPP were detected, and the same over-activation of Rab5 could also be observed in AD brains (Kim et al, 2016). The C-terminal fragment produced after cleavage by α-secretase, C83, has no known function but it has been implicated as being involved in neurodegeneration (Rockenstein et al, 2005).…”

“…The underlying cause of accumulation of AVs in AD is believed to be a disruption in the proteolytic clearance of these vesicles by lysosomes. The C-terminal fragment produced after BACE1 cleavage of AβPP can pathologically activate Rab5, leading to swelling of endosomes (Kim et al, 2016). Neurons are postmitotic, leaving them more vulnerable to a potential toxic build-up from waste that the endosomes and lysosomes fail to degrade.…”