Significance of transcytosis in Alzheimer's disease: BACE1 takes the scenic route to axons

Buggia-Prévot, Virginie; Wang, Shuai

doi:10.1002/bies.201500019

Cited by 12 publications

(4 citation statements)

References 94 publications

(140 reference statements)

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“…S-palmitoylation has also been recognized as the signal that directs sorting of GRIP1b and AKAP 79/150 to recycling endosomes in dendrites and GAD65 to axonspecific endosomes (56)(57)(58). Taken together with our previous characterization of dendrite-to-axon transcytosis of BACE1, mediated by EHD1/3 and Rab11-dependent endocytic sorting (22,37,38), the remarkable differences in dendritic spine localization and axonal targeting of wt and 4CA-BACE1 in cultured hippocampal neurons suggest a potential mechanistic link between S-palmitoylation and polarized sorting of BACE1 in endosomes.…”

Section: Discussionsupporting

confidence: 72%

“…BACE1 undergoes polarized sorting in vivo and in transfected hippocampal neurons (22,37). BACE1 targeting to axons involves a transcytotic mechanism whereby BACE1 is internalized from dendrites and trafficked in an exclusively retrograde direction to the soma and subsequently routed to the axon in a Rab11-dependent manner (22,37,38). Therefore, axonal localization of BACE1 was quantified to assess whether there is a deficiency in axonal targeting of 4CA-YFP.…”

Section: S-palmitoylation Is Required For Bace1 Localization In Neuromentioning

confidence: 99%

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Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer’s disease

Andrew

Fernandez

Stanley

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by pathological brain lesions and a decline in cognitive function. β-Amyloid peptides (Aβ), derived from proteolytic processing of amyloid precursor protein (APP), play a central role in AD pathogenesis. β-Site APP cleaving enzyme 1 (BACE1), the transmembrane aspartyl protease which initiates Aβ production, is axonally transported in neurons and accumulates in dystrophic neurites near cerebral amyloid deposits in AD. BACE1 is modified by S-palmitoylation at four juxtamembrane cysteine residues. S-palmitoylation is a dynamic posttranslational modification that is important for trafficking and function of several synaptic proteins. Here, we investigated the in vivo significance of BACE1 S-palmitoylation through the analysis of knock-in mice with cysteine-to-alanine substitution at the palmitoylated residues (4CA mice). BACE1 expression, as well as processing of APP and other neuronal substrates, was unaltered in 4CA mice despite the lack of BACE1 S-palmitoylation and reduced lipid raft association. Whereas steady-state Aβ levels were similar, synaptic activity-induced endogenous Aβ production was not observed in 4CA mice. Furthermore, we report a significant reduction of cerebral amyloid burden and BACE1 accumulation in dystrophic neurites in the absence of BACE1 S-palmitoylation in mouse models of AD amyloidosis. Studies in cultured neurons suggest that S-palmitoylation is required for dendritic spine localization and axonal targeting of BACE1. Finally, the lack of BACE1 S-palmitoylation mitigates cognitive deficits in 5XFAD mice. Using transgenic mouse models, these results demonstrate that intrinsic posttranslational S-palmitoylation of BACE1 has a significant impact on amyloid pathogenesis and the consequent cognitive decline.

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Section: Discussionsupporting

confidence: 72%

Section: S-palmitoylation Is Required For Bace1 Localization In Neuromentioning

confidence: 99%

Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer’s disease

Andrew

Fernandez

Stanley

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…By using biochemical and electron microscopy approaches, the protein components for Aβ generation, such as APP (Vassar and Zheng, 2014), BACE1 (Buggia-Prevot and Thinakaran, 2015), and γ-secretase (DeBoer et al, 2014; Haass et al, 2012), have all been found in the presynaptic site and Aβ can be released locally to impact postsynaptic functions (Figure 2). The lumen of presynaptic vesicles is acidic (pH=5.6), which is compatible with favored BACE1 processing under moderate acidic conditions.…”

Section: Aβ and Synaptic Functionsmentioning

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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“…In non-neuronal cells, cargo from early endosomes can recycle directly to the cell surface via a Rab4-mediated route or can be targeted to the cell surface via a Rab11-mediated recycling route via the perinuclear compartment [ 69 ]. Substantial evidence indicates that in neurons Rab11-positive endosomes are involved in the targeting of BACE1 from dendrites to axons through the soma resulting in a concomitant reduction in the dendritic pool of BACE1 available for recycling [ 24 , 25 , 70 ]. Overexpression of the NCAM2 fragment consisting of the transmembrane and intracellular domains of NCAM2 in CHO cells or cultured neurons leads to an increase in BACE1 levels in Rab11-positive endosomes, indicating that the BACE1-generated NCAM2 cleavage product can target BACE1 to Rab11-positive recycling endosomes.…”

Section: Discussionmentioning

confidence: 99%

The BACE1-generated C-terminal fragment of the neural cell adhesion molecule 2 (NCAM2) promotes BACE1 targeting to Rab11-positive endosomes

Keable

Pfundstein

et al. 2022

Cell. Mol. Life Sci.

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Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as β-secretase, is an aspartic protease. The sorting of this enzyme into Rab11-positive recycling endosomes regulates the BACE1-mediated cleavage of its substrates, however, the mechanisms underlying this targeting remain poorly understood. The neural cell adhesion molecule 2 (NCAM2) is a substrate of BACE1. We show that BACE1 cleaves NCAM2 in cultured hippocampal neurons and NCAM2-transfected CHO cells. The C-terminal fragment of NCAM2 that comprises the intracellular domain and a small portion of NCAM2’s extracellular domain, associates with BACE1. This association is not affected in cells with inhibited endocytosis, indicating that the interaction of NCAM2 and BACE1 precedes the targeting of BACE1 from the cell surface to endosomes. In neurons and CHO cells, this fragment and BACE1 co-localize in Rab11-positive endosomes. Overexpression of full-length NCAM2 or a recombinant NCAM2 fragment containing the transmembrane and intracellular domains but lacking the extracellular domain leads to an increase in BACE1 levels in these organelles. In NCAM2-deficient neurons, the levels of BACE1 are increased at the cell surface and reduced in intracellular organelles. These effects are correlated with increased levels of the soluble extracellular domain of BACE1 in the brains of NCAM2-deficient mice, suggesting increased shedding of BACE1 from the cell surface. Of note, shedding of the extracellular domain of Sez6, a protein cleaved exclusively by BACE1, is reduced in NCAM2-deficient animals. These results indicate that the BACE1-generated fragment of NCAM2 regulates BACE1 activity by promoting the targeting of BACE1 to Rab11-positive endosomes.

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Significance of transcytosis in Alzheimer's disease: BACE1 takes the scenic route to axons

Cited by 12 publications

References 94 publications

Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer’s disease

Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer’s disease

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

The BACE1-generated C-terminal fragment of the neural cell adhesion molecule 2 (NCAM2) promotes BACE1 targeting to Rab11-positive endosomes

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