A Function for EHD Family Proteins in Unidirectional Retrograde Dendritic Transport of BACE1 and Alzheimer’s Disease Aβ Production

Buggia-Prévot, Virginie; Fernandez, Celia G.; Udayar, Vinod; Vetrivel, Kulandaivelu S.; Elie, Auréliane; Roseman, Jelita; Sasse, V.A.; Lefkow, Margaret; Meckler, Xavier; Bhattacharyya, Sohinee; George, Manju; Kar, Satyabrata; Bindokas, Vytautas P.; Parent, Angèle; Rajendran, Lawrence; Band, Hamid; Vassar, Robert; Wang, Shuai

doi:10.1016/j.celrep.2013.12.006

Cited by 65 publications

(89 citation statements)

References 46 publications

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“…A slight but statistically significant decrease in anterogradely trafficking BACE1 vesicles was also observed (Fig. 1f), which is consistent with data showing that endocytosed BACE1 undergo bidirectional axonal trafficking (Buggia-Prevot et al, 2013). …”

Section: Resultssupporting

confidence: 90%

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

Sun

Zhang

2017

Neurobiology of Aging

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The cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) is the rate limiting step in the generation of β-amyloid (Aβ) during Alzheimer’s disease (AD) pathogenesis. In AD brains, BACE1 is abnormally accumulated in the endocytic compartments, where the acidic pH is optimal for its activity. However mechanisms that regulate the endosome-to-TGN retrieval of BACE1 under physiological conditions remain unclear. Here we show the Par polarity complex containing Par3 and aPKC facilitates BACE1 retrograde trafficking from the endosomes to the TGN. We further show that Par3 functions through aPKC-mediated phosphorylation of BACE1 on Ser498. Finally, we found that Ser498 phosphorylation promotes the interaction between BACE1 and PACS1, which is necessary for the retrograde trafficking of BACE1 to the TGN. In human AD brains, there is a significant decrease in Ser498 phosphorylation of BACE1 suggesting that defective phosphorylation-dependent retrograde transport of BACE1 is important in the AD pathogenic process. Together, our studies provide mechanistic insight into a novel role for Par3 and aPKC in regulating the retrograde endosome-to-TGN trafficking of BACE1, and shed light on the mechanisms of AD pathogenesis.

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Section: Resultssupporting

confidence: 90%

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

Sun

Zhang

2017

Neurobiology of Aging

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“…In this regard, presenilin, the catalytic component of the ␥-secretase complex, is distributed within both axons and the somatodendritic domain, but at very low levels on the cell surface (Cook et al, 1996;Kovacs et al, 1996;Busciglio et al, 1997). Similarly, BACE is also distributed within both axons and dendrites in vitro, but is highly polarized to axonal domains in vivo (Capell, 2002;Buggia-Prévot et al, 2013). ADAM10, the presumptive constitutive neuronal ␣-secretase, is found in dendrites at the postsynaptic density (Marcello et al, 2007) and within axons (Szodorai et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Differential Release of β-Amyloid from Dendrite- Versus Axon-Targeted APP

DeBoer¹,

Dolios

Wang

et al. 2014

J. Neurosci.

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The ␤-amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's disease. APP is processed in neurons, but little is known about the relative contributions of presynaptic or postsynaptic compartments to the release of A␤ peptides. To address this issue, we transduced primary neurons from Sprague-Dawley rats or APP Ϫ/Ϫ mice (B6.129S7-App tm1Dbo /J) with lentiviral constructs expressing APP chimeras harboring targeting motifs from low-density lipoprotein receptor or neuron-glia cell-adhesion molecule to polarize expression to either dendritic or axonal membranes, respectively. Using imaging and quantitative biochemical approaches, we now report that APP selectively targeted to either axons or dendrites leads to the secretion of full-length A␤ peptides with significantly elevated release from dendritic compartments. These findings reveal that the enzymatic machinery required for production of A␤ peptides are operative both in presynaptic and postsynaptic compartments of primary neurons, leading to the suggestion that A␤-mediated impairments in glutamatergic neurotransmission is the result of A␤ release from both local and distal neuronal compartments.

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“…Depletion of both GGA1 and GGA3 induces a rapid and robust elevation of BACE1, and such an effect will likely be interfered with by flotillin, which can compete with GGA proteins for binding to the same dileucine motif in the BACE1 tail (John et al, 2014). In neurons, BACE1 is targeted to both axons and dendrites, and its preferential transport to the axonal terminus versus somatodendrites can be regulated by altered levels of calsyntenin-1 (Steuble et al, 2012; Vagnoni et al, 2012), retromer vps35 (Wang et al, 2012a; Wen et al, 2011), RTN3 (Deng et al, 2013), Rab11, and Eps15 homology domain proteins (Buggia-Prevot et al, 2014; Buggia-Prevot et al, 2013; Udayar et al, 2013). The localization of BACE1 in synaptic sites can impact the processing of its substrates.…”

Section: Brief Overview Of Bace1mentioning

confidence: 99%

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

Yan

Fan

Zhou

et al. 2016

Neuroscience & Biobehavioral Reviews

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Over the past two decades, many studies have identified significant contributions of toxic β-amyloid peptides (Aβ) to the etiology of Alzheimer’s disease (AD), which is the most common age-dependent neurodegenerative disease. AD is also recognized as a disease of synaptic failure. Aβ, generated by sequential proteolytic cleavages of amyloid precursor protein (APP) by BACE1 and γ-secretase, is one of major culprits that cause this failure. In this review, we summarize current findings on how BACE1-cleaved APP products impact learning and memory through proteins localized on glutamatergic, GABAergic, and dopaminergic synapses. Considering the broad effects of Aβ on all three types of synapses, BACE1 inhibition emerges as a practical approach for ameliorating Aβ-mediated synaptic dysfunctions. Since BACE1 inhibitory drugs are currently in clinical trials, this review also discusses potential complications arising from BACE1 inhibition. We emphasize that the benefits of BACE1 inhibitory drugs will outweigh the concerns.

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A Function for EHD Family Proteins in Unidirectional Retrograde Dendritic Transport of BACE1 and Alzheimer’s Disease Aβ Production

Cited by 65 publications

References 46 publications

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

Differential Release of β-Amyloid from Dendrite- Versus Axon-Targeted APP

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

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