Implications of cell surface expression of the Alzheimer's beta-amyloid precursor protein

Regulation of AMPA receptor expression by neuronal activity and neuromodulators is critical to the expression of both long-term potentiation (LTP) and memory. In particular, Ca2+-permeable AMPARs (CP-AMPAR) play a unique role in these processes due to their transient, activity-regulated expression at synapses. Secreted amyloid precursor protein-alpha (sAPPα), a metabolite of the parent amyloid precursor protein (APP) has been previously shown to enhance hippocampal LTP as well as memory formation in both normal animals and in Alzheimer’s disease models. In earlier work we showed that sAPPα promotes trafficking of GluA1-containing AMPARs to the cell surface and specifically enhances synthesis of GluA1. To date it is not known whether de novo synthesized GluA1 form CP-AMPARs or how they contribute to sAPPα-mediated plasticity. Here, using fluorescent non-canonical amino acid tagging–proximity ligation assay (FUNCAT-PLA), we show that brief treatment of primary rat hippocampal neurons with sAPPα (1 nM, 30 min) rapidly enhanced the cell-surface expression of de novo GluA1 homomers and reduced levels of de novo GluA2, as well as extant GluA2/3-AMPARs. The de novo GluA1-containing AMPARs were localized to extrasynaptic sites and later internalized by sAPPα-driven expression of the activity-regulated cytoskeletal-associated protein, Arc. Interestingly, longer exposure to sAPPα increased synaptic levels of GluA1/2 AMPARs. Moreover, the sAPPα-mediated enhancement of LTP in area CA1 of acute hippocampal slices was dependent on CP-AMPARs. Together, these findings show that sAPPα engages mechanisms which specifically enhance the synthesis and cell-surface expression of GluA1 homomers, underpinning the sAPPα-driven enhancement of synaptic plasticity in the hippocampus.

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Neuregulin 1 regulates amyloid precursor protein cell surface expression and non-amyloidogenic processing

Journal of Pharmacological Sciences ◽

10.1016/j.jphs.2018.05.004 ◽

2018 ◽

Vol 137 (2) ◽

pp. 146-153 ◽

Cited By ~ 2

Author(s):

Young-Jung Kim ◽

Ji-Young Yoo ◽

Ok-Soon Kim ◽

Han-byeol Kim ◽

Junghwa Ryu ◽

...

Keyword(s):

Cell Surface ◽

Amyloid Precursor Protein ◽

Surface Expression ◽

Precursor Protein ◽

Cell Surface Expression ◽

Neuregulin 1 ◽

Amyloidogenic Processing ◽

Protein Cell

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Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons.

The Journal of Cell Biology ◽

10.1083/jcb.129.2.431 ◽

1995 ◽

Vol 129 (2) ◽

pp. 431-442 ◽

Cited By ~ 136

Author(s):

T Yamazaki ◽

D J Selkoe ◽

E H Koo

Keyword(s):

Cell Surface ◽

Amyloid Precursor Protein ◽

Hippocampal Neurons ◽

Mdck Cells ◽

Sympathetic Neurons ◽

Senile Plaques ◽

Indirect Evidence ◽

Beta Amyloid ◽

Precursor Protein ◽

Cultured Neurons

Amyloid beta-protein (A beta), the principal constituent of senile plaques seen in Alzheimer's disease (AD), is derived by proteolysis from the beta-amyloid precursor protein (beta PP). The mechanism of A beta production in neurons, which are hypothesized to be a rich source of A beta in brain, remains to be defined. In this study, we describe a detailed localization of cell surface beta PP and its subsequent trafficking in primary cultured neurons. Full-length cell surface beta PP was present primarily on perikarya and axons, the latter with a characteristic discontinuous pattern. At growth cones, cell surface beta PP was inconsistently detected. By visualizing the distribution of beta PP monoclonal antibodies added to intact cultures, beta PP was shown to be internalized from distal axons or terminals and retrogradely transported back to perikarya in organelles which colocalized with fluid-phase endocytic markers. Retrograde transport of beta PP was shown in both hippocampal and peripheral sympathetic neurons, the latter using a compartment culture system that isolated cell bodies from distal axons and terminals. In addition, we demonstrated that beta PP from distal axons was transcytotically transported to the surface of perikarya from distal axons in sympathetic neurons. Indirect evidence of this transcytotic pathway was obtained in hippocampal neurons using antisense oligonucleotide to the kinesin heavy chain to inhibit anterograde beta PP transport. Taken together, these results demonstrate novel aspects of beta PP trafficking in neurons, including retrograde axonal transport and transcytosis. Moreover, the axonal predominance of cell surface beta PP is unexpected in view of the recent report of polarized sorting of beta PP to the basolateral domain of MDCK cells.

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Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner

Journal of Neuroscience ◽

10.1523/jneurosci.15-03-02157.1995 ◽

1995 ◽

Vol 15 (3) ◽

pp. 2157-2167 ◽

Cited By ~ 119

Author(s):

WQ Qiu ◽

A Ferreira ◽

C Miller ◽

EH Koo ◽

DJ Selkoe

Keyword(s):

Cell Surface ◽

Amyloid Precursor Protein ◽

Neurite Outgrowth ◽

Hippocampal Neurons ◽

Beta Amyloid ◽

Precursor Protein ◽

Dependent Manner

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Trafficking of cell-surface amyloid beta-protein precursor. I. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody

Journal of Cell Science ◽

10.1242/jcs.109.5.991 ◽

1996 ◽

Vol 109 (5) ◽

pp. 991-998 ◽

Cited By ~ 7

Author(s):

E.H. Koo ◽

S.L. Squazzo ◽

D.J. Selkoe ◽

C.H. Koo

Keyword(s):

Monoclonal Antibody ◽

Cell Surface ◽

Amyloid Precursor Protein ◽

Amyloid Beta ◽

Senile Plaques ◽

Beta Amyloid ◽

Precursor Protein ◽

Secretory Product ◽

Amyloid Beta Protein ◽

Lysosomal Compartment

Amyloid beta-protein, the principal constituent of amyloid fibrils found in senile plaques and blood vessels in Alzheimer's disease, is constitutively produced and released into medium of cultured cells. Amyloid beta-protein is derived by proteolysis of the beta-amyloid precursor protein by unclear mechanisms. Beta-amyloid precursor protein is a transmembrane protein which can be processed to release a large secretory product or processed in the endosomal/lysosomal pathway without secretion. Previous studies have shown that from the cell surface, beta-amyloid precursor protein may be released after cleavage or internalized without cleavage, the latter in a pathway that both produces amyloid beta-protein and also targets some molecules to the lysosomal compartment. Analysis of beta-amyloid precursor protein trafficking is confounded by the concomitant secretion and internalization of molecules from the cell surface. To address this issue, we developed an assay, based on the binding of radioiodinated monoclonal antibody, to measure the release and internalization of cell surface beta-amyloid precursor protein in transfected cells. With this approach, we showed that surface beta-amyloid precursor protein is either rapidly released or internalized, such that the duration at the cell surface is very short. Approximately 30% of cell surface beta-amyloid precursor protein molecules are released. Following internalization, a fraction of molecules are recycled while the majority of molecules are rapidly sorted to the lysosomal compartment for degradation When the C terminus of beta-amyloid precursor protein is deleted, secretion is increased by approximately 2.5-fold as compared to wild-type molecules. There is concomitant decrease in internalization in these mutant molecules as well as prolongation of the resident time on the cell surface. This observation is consistent with recent evidence that signals within the cytoplasmic domain mediate beta-amyloid precursor protein internalization.

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Beta amyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion

Journal of Neuroscience Research ◽

10.1002/jnr.490280109 ◽

1991 ◽

Vol 28 (1) ◽

pp. 90-100 ◽

Cited By ~ 182

Author(s):

K. C. Breen ◽

M. Bruce ◽

B. H. Anderton

Keyword(s):

Cell Surface ◽

Amyloid Precursor Protein ◽

Neuronal Cell ◽

Beta Amyloid ◽

Precursor Protein ◽

Surface Adhesion ◽

Cell Cell

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Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis

Journal of Endocrinology ◽

10.1677/joe-08-0005 ◽

2008 ◽

Vol 198 (2) ◽

pp. 291-299 ◽

Cited By ~ 31

Author(s):

Kerstin Krause ◽

Stefan Karger ◽

Sien-Yi Sheu ◽

Thomas Aigner ◽

Romy Kursawe ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Surface Expression ◽

Precursor Protein ◽

Cell Surface Expression ◽

Prolonged Release ◽

Mrna Levels ◽

Thyroid Cells ◽

And Function

We have recently found an increased expression of amyloid precursor protein (APP) in cold thyroid nodules that are difficult to classify as a truly benign thyroid neoplasm or a lesion with the potential for further dedifferentiation. Since differences in APP activity have been found in other human cancers, we asked whether thyroid carcinogenesis might be associated with an altered APP expression and function. APP regulation was studied in vitro in differentiated (FRTL-5) and dedifferentiated follicular thyroid carcinomas (FTC-133) thyroid cells after specific inhibition or activation of the cAMP-PKA, the PI3K/AKT or the protein kinase c (PKC) cascades. In vivo analysis of APP expression and downstream signalling was performed in benign and malignant thyroid tissues. We found that upregulation of APP expression and sAPP secretion is induced by TSH in differentiated thyroid cells and by insulin in thyroid cancer cells. PKC is a strong activator of APP cleavage and in FTC-133 confers prolonged release of the APP ectodomain. FTC-133 but not FRTL-5 cells show a prominent cell surface expression of the APP ectodomain, which has been suggested to function as an autocrine growth factor. Thyroid cancers are characterized by APP upregulation, increased membrane targeting of the APP ectodomain and significantly increased mRNA levels of the APP scaffold proteins JIP1, ShcA and Fe65.

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Polarized sorting of beta-amyloid precursor protein and its proteolytic products in MDCK cells is regulated by two independent signals.

The Journal of Cell Biology ◽

10.1083/jcb.128.4.537 ◽

1995 ◽

Vol 128 (4) ◽

pp. 537-547 ◽

Cited By ~ 94

Author(s):

C Haass ◽

E H Koo ◽

A Capell ◽

D B Teplow ◽

D J Selkoe

Keyword(s):

Amino Acids ◽

Cell Surface ◽

Amyloid Precursor Protein ◽

Mdck Cells ◽

Membrane Vesicles ◽

Beta Amyloid ◽

Precursor Protein ◽

Amyloid A ◽

Membrane Spanning ◽

Chloride Treatment

Progressive cerebral deposition of the amyloid (A beta) beta-protein is an early and invariant feature of Alzheimer's disease. A beta is derived by proteolysis from the membrane-spanning beta-amyloid precursor protein (beta APP). beta APP is processed into various secreted products, including soluble beta APP (APPs), the 4-kD A beta peptide, and a related 3-kD peptide (p3). We analyzed the mechanisms regulating the polarized basolateral sorting of beta APP and its proteolytic derivatives in MDCK cells. Deletion of the last 32 amino acids (residues 664-695) of the beta APP cytoplasmic tail had no influence on either the constitutive approximately 90% level of basolateral sorting of surface beta APP, or the strong basolateral secretion of APPs, A beta, and p3. However, deleting the last 42 amino acids (residues 654-695) or changing tyrosine 653 to alanine altered the distribution of cell surface beta APP so that approximately 40-50% of the molecules were inserted apically. In parallel, A beta was now secreted from both surfaces. Surprisingly, this change in surface beta APP had no influence on the basolateral secretion of APPs and p3. This result suggests that most beta APP molecules which give rise to APPs in MDCK cells are cleaved intracellularly before reaching the surface. Consistent with this conclusion, we readily detected intracellular APPs in carbonate extracts of isolated membrane vesicles. Moreover, ammonium chloride treatment resulted in the equal secretion of APPs into both compartments, as occurs with other non-membranous, basolaterally secreted proteins, but it did not influence the polarity of cell surface beta APP. These results demonstrate that in epithelial cells two independent mechanisms mediate the polarized trafficking of beta APP holoprotein and its major secreted derivative (APPs) and that A beta peptides are derived in part from beta APP holoprotein targeted to the cell surface by a signal that includes tyrosine 653.

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