Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer’s Disease

Pensalfini, Anna; Kim, Seonil; Subbanna, Shivakumar; Bleiwas, Cynthia; Goulbourne, Chris N.; Stavrides, Philip; Jiang, Ying; Lee, Ju‐Hyun; Darji, Sandipkumar; Pawlik, Monika; Huo, Chunfeng; Peddy, James; Berg, Martin J.; Smiley, John F.; Basavarajappa, Balapal S.; Nixon, Ralph A.

doi:10.1016/j.celrep.2020.108420

Cited by 74 publications

(68 citation statements)

References 120 publications

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“…Degradative pathways that direct cargos to the lysosome include autophagosome-lysosome and endosome-lysosome pathways, both of which are highly regulated, vacuolar-based degradative systems. Although dysfunction of the autophagy pathway is likely one of the contributors to neurodegenerative proteopathies such as AD and Parkinson's disease [52,11], it is clear that impairment of the endosome-lysosome pathway is also a significant contributor to the pathogenesis of these diseases [75,61]. The endosome-lysosome pathway is an important protein clearance mechanism that directs the engulfment of protein cargo and trafficking to the lysosome for degradation.…”

Section: Introductionmentioning

confidence: 99%

BAG3 regulation of Rab35 mediates the Endosomal Sorting Complexes Required for Transport /endolysosome pathway and tau clearance

Lin

Tang

et al. 2021

Preprint

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The decline in proteostasis during aging is a major contributing factor to increased susceptibility to neurodegenerative diseases such as Alzheimer’s disease. Although dysfunction of the autophagy pathway is likely one of the contributors, emerging studies implicate that impairment of the endosome-lysosome pathway is also a significant factor in the pathogenesis of these diseases. Our lab was the first to demonstrate that BAG3 facilitates phosphorylated tau clearance through autophagy. However, we did not fully define the mechanisms by which BAG3 regulates endogenous tau proteostasis. Here, we applied mass spectrometric analyses and found a major group of neuronal BAG3 interactors are in the endocytic pathway. Among them were key regulators of small GTPases. Excitingly one of these was the Rab35 GTPase activating protein, TBC1D10B. Our data demonstrate that a BAG3-HSP70-TBC1D10B complex attenuates the ability of TBC1D10B to inactivate Rab35. Thus BAG3, through its interaction with TBC1D10B supports the activation of Rab35 and recruitment of Hrs, which initiates ESCRT-mediated endosomal tau clearance. Further, intrahippocampal expression of BAG3 in P301S mice increased the co-localization of phospho-tau with the ESCRT III protein CHMP2B and reduced the levels of the mutant human tau. Overall, our data provide evidence of a novel BAG3-TBC1D10B-Rab35 regulatory axis in modulating vacuolar dependent protein degradation machinery through ESCRT. These findings expand our understanding of the role of BAG3 in neuronal proteostasis, and how dysregulation could contribute to the pathogenesis of Alzheimer’s disease, as well as other neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

BAG3 regulation of Rab35 mediates the Endosomal Sorting Complexes Required for Transport /endolysosome pathway and tau clearance

Lin

Tang

et al. 2021

Preprint

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“…The second possible mechanism is Rab5 activation. Previous reports, using Rab5A constitutively active mutant (Q79L) 33 and overexpressing mice 34 , showed Rab5 positive enlarged endosomes. Additionally, elevated βCTF can form a complex with APPL1, a Rab5 effector protein, which mediates Rab5 activation and endosome enlargement in DS fibroblasts and AD brains 10 .…”

Section: Discussionmentioning

confidence: 81%

Lipid flippase dysfunction as a novel therapeutic target for endosomal anomalies in Alzheimer’s disease

Kaneshiro

Komai

Imaoka

et al. 2021

Preprint

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β-amyloid precursor protein (APP) and their metabolites are deeply involved in the development of Alzheimer's disease (AD). Upon the upregulation of β-site APP cleaving enzyme 1 (BACE1), its product, the β-carboxyl-terminal fragment of APP (βCTF), is accumulated in the early stage of sporadic AD brains. βCTF accumulation is currently considered the trigger for endosomal anomalies to form enlarged endosomes, one of the earliest pathologies in AD. However, the details of the underlying mechanism remain largely unclear. In this study, using BACE1 stably-overexpressing cells, we describe that lipid flippase subcomponent TMEM30A interacts with accumulated βCTF. Among the lipid flippases in endosomes, those composed of TMEM30A and active subcomponent ATP8A1 transports phospholipid, phosphatidylserine (PS), to the cytosolic side of the endosomes. The lipid flippase activity and cytosolic PS distribution are critical for membrane fission and vesicle transport. Intriguingly, accumulated βCTF in model cells impaired lipid flippase physiological formation and activity, along with endosome enlargement. Moreover, in the brains of AD model mice before the amyloid-β (Aβ) deposition, the TMEM30A/βCTF complex formation occurred, followed by lipid flippase dysfunction. Importantly, our novel Aβ/βCTF interacting TMEM30A-derived peptide "T-RAP" improved endosome enlargement and reduced βCTF levels. These T-RAP effects could result from the recovery of lipid flippase activity. Therefore, we propose lipid flippase dysfunction as a key pathogenic event and a novel therapeutic target for AD.

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“…Our findings now provide a mechanistic explanation how ApoE4 impairs endolysosomal trafficking and recycling, by interfering with vesicular sorting and maturation at a crucial bottleneck juncture of the endosomal trafficking machinery. This has far-reaching consequences for neuronal function, synaptic plasticity, and tau phosphorylation (Brich et al, 2003;Cataldo et al, 2000;Chen et al, 2005;Chen et al, 2010;Nuriel et al, 2017;Pensalfini et al, 2020). More specifically, ApoE4 causes abnormalities of Rab5-positive endosomes (Nuriel et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, over-activation of the small guanosine triphosphatase (GTPase) Rab5, recapitulates neurodegenerative features of AD (Pensalfini et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load

Pohlkamp

Xian

Wong

et al. 2021

eLife

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Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer's disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger 6 (NHE6) restores vesicular trafficking and normalizes synaptic homeostasis. Remarkably and unexpectedly, loss of NHE6 (encoded by the gene Slc9a6) in mice effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of early endosomes caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation. NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4 induced endolysosomal trafficking defect and reduces plaque load.

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Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer’s Disease

Cited by 74 publications

References 120 publications

BAG3 regulation of Rab35 mediates the Endosomal Sorting Complexes Required for Transport /endolysosome pathway and tau clearance

BAG3 regulation of Rab35 mediates the Endosomal Sorting Complexes Required for Transport /endolysosome pathway and tau clearance

Lipid flippase dysfunction as a novel therapeutic target for endosomal anomalies in Alzheimer’s disease

NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load

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