Soluble amyloid precursor protein: a novel proliferation factor of adult progenitor cells of ectodermal and mesodermal origin
© Demars et al.; licensee BioMed Central Ltd. 2011
Received: 1 July 2011
Accepted: 30 August 2011
Published: 30 August 2011
Soluble amyloid precursor protein α (sAPPα) is a proteolyte of APP cleavage by α-secretase. The significance of the cleavage and the physiological role of sAPPα are unknown. A crystal structure of a region of the amino terminal of sAPPα reveals a domain that is similar to cysteine-rich growth factors. While a previous study implicates sAPPα in the regulation of neural progenitor cell proliferation in the subventricular zone of adult mice, the ubiquitous expression of APP suggests that its role as a growth factor might be broader.
sAPPα and α-secretase activities were determined in neural progenitor cells (NPCs), mesenchymal stem cells (MSC) and human decidua parietalis placenta stem cells (hdPSC). Inhibition of α-secretase was achieved by treatment with the matrixmetalloproteinase inhibitor GM6001, and proliferation was determined using clonogenic and immunocytochemical analysis of cell-lineage markers. Recovery of proliferation was achieved by supplementing GM6001-treated cells with recombinant soluble APPα. Expression of APP and its cellular localization in the subventricular zone was determined by Western blot and immunohistochemical analyses of APP wild type and knockout tissue. Alterations in pERK and pAKT expression as a function of soluble APPα production and activity in NPCs were determined by Western blot analysis.
Here we show that sAPPα is a proliferation factor of adult NPCs, MSCs and hdpPSC. Inhibition of α-secretase activity reduces proliferation of these stem cell populations in a dose-dependent manner. Stem cell proliferation can be recovered by the addition of sAPPα in a dose-dependent manner, but not of media depleted of sAPPα. Importantly, sAPPα operates independently of the prominent proliferation factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), but in association with ERK signaling and MAP-kinase signaling pathways. Levels of sAPPα and putative α-secretase, ADAM10, are particularly high in the subventricular zone of adult mice, suggesting a role for sAPPα in regulation of NPCs in this microenvironment.
These results determine a physiological function for sAPPα and identify a new proliferation factor of progenitor cells of ectodermal and mesodermal origin. Further, our studies elucidate a potential pathway for sAPPα signaling through MAP kinase activation.
Amyloid precursor proteins (APPs) comprise a family of evolutionarily conserved single-pass type I transmembrane glycoproteins of an unknown physiological function. In mammals, that family includes APP and amyloid precursor-like protein 1 and 2 (APLP1 and APLP2) (reviewed in ). Mutations in APP cause familial Alzheimer's disease (reviewed in ). APP undergoes extensive enzymatic processing, producing both intracellular and extracellular metabolites (reviewed in ). In its non-amyloidogenic pathway, APP is cleaved mostly on the plasma membrane by an enzymatic activity termed the α-secretase [3, 4]. α-Secretase cleaves APP between Lys16 and Leu17 of the Aβ region, resulting in the release of a soluble fragment (sAPPα) to the extracellular lumen and the retention of a membrane-tethered carboxyl-terminus fragment that undergoes further proteolysis (reviewed in ). The identity of α-secretase is not fully elucidated. Several enzymes-including members of the ADAM (a disintegrin and metalloproteinase) family ADAM10 , ADAM17 (TACE) [6–9], and ADAM9 as well as aspartyl protease beta-site APP-cleaving enzyme 2 (BACE2) -are known to have α-secretase activity. Like APP, APLP2 is a substrate of ADAM10 and 17 . Both ADAM10 and 17 are implicated in development-regulated notch signaling by ectodomain shedding of Notch ligands Delta and Jagged . ADAM10 was recently suggested to be the main α-secretase in the brain .
sAPPα has been shown to exhibit neurotrophic and proliferative properties in fibroblasts , thyroid epithelial cells , and embryonic stem cells . A crystal structure of a region of the amino terminal of sAPPα also reveals a domain that is similar to cysteine-rich growth factors, suggesting that sAPPα may act as a potential ligand for growth factor receptors . Indeed, epidermal growth factor (EGF)-responsive neural progenitor cells (NPCs) in the subventricular zone (SVZ) have been shown to have binding sites for sAPP . Deficiency of the sortilin-related receptor with type-A repeats (SORLA) results in enhancement of sAPP production, extracellular signal-regulated kinase (ERK) stimulation, and increased proliferation and survival of NPCs in both the SVZ and subgranular layer of the dentate gyrus (SGL) . Taken together, these results suggest that APP may act as a growth factor in promoting cellular proliferation. However, there has been no follow-up to these studies. It is not clear what populations of NPCs sAPPα acts upon, whether it is a stand-alone factor or a co-factor, or whether it regulates non-neural adult stem cell populations.
Here, we show that the production of sAPPα by α-secretase processing of APP is an important event for the promotion of proliferation in a wide range of stem cell populations. We show, specifically, that sAPPα regulates the proliferation of NPCs, mesenchymal stem cells (MSCs), and Human decidua parietalis placenta stem cells (hdpPSCs). Importantly, sAPPα is a stand-alone proliferation factor, exerting its proliferative effect in an EGF- and basic fibroblast growth factor (bFGF)-independent manner. In the brain, levels of sAPPα are particularly high in the SVZ. In addition, we show that, in NPCs, sAPPα function is associated with the ERK signaling pathway. These results suggest that sAPPα is an essential proliferation factor for neural and non-neural adult stem cells. These observations further provide a functional significance for the abundance of APP.
Materials and methods
Primary neurosphere culture
Two-month-old C57/Bl6 wild-type mice were euthanized and their brains were removed and placed into sterile Dulbecco's modified Eagle's medium/F12 (DMEM/F12). A coronal slice (approximately 1 mm) was dissected starting 1 to 2 mm posterior to the olfactory bulb. The region occupying the lateral wall and anterior horn of the lateral ventricles was removed with the aid of a dissecting microscope and diced with a sterile scalpel. Neurosphere culture was prepared as previously described . Briefly, tissue pieces were collected in a mixture of Papain and DNase in Earl's balanced salt solution and incubated at 37°C for 40 minutes. Then, tissue pieces were pelleted by centrifugation and dissociated to a single-cell suspension, and cells were plated in complete medium-water, DMEM/F12 (Gibco, now part of Invitrogen Corporation, Carlsbad, CA, USA), glucose (Sigma-Aldrich, St. Louis, MO, USA), NaHCO3 (Sigma-Aldrich), HEPES (Sigma-Aldrich), L-glutamine (Invitrogen Corporation), penicillin/streptomycin (Invitrogen Corporation), putrescine (9.6 μg/mL; Sigma-Aldrich), apotransferrin (0.1 mg/mL; Sigma-Aldrich), insulin (0.025 mg/mL; Roche, Indianapolis, IN, USA), selenium (5.2 ng/mL; Sigma-Aldrich), progesterone (6.3 ng/mL; Sigma-Aldrich), bovine serum albumin (BSA) (2 mg/mL; Sigma-Aldrich), heparin (4 μg/mL; Sigma-Aldrich), EGF (20 ng/mL; PeproTech, Rocky Hill, NJ, USA), and bFGF (10 ng/mL; PeproTech)-and passaged after 10 days.
Isolation of mesenchymal stem cells
After euthanasia, the bone marrow contents of the femurs and tibia of donor Balb/C mice were flushed through a 40-μm filter (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) into a 50-mL tube (Corning, Corning, NY, USA) containing MSC media: 40% alpha-modified Eagle's medium (Invitrogen Corporation, Rockville, MD, USA), 40% F-12 nutrient mixture (Invitrogen Corporation), 10% fetal bovine serum (Valley Biomedical, Winchester, VA, USA), and 1% antibiotic-antimycotic solution (Invitrogen Corporation). Bone marrow cells were plated at a density of 20 × 106 per 9.6 cm2 in MSC media at 37°C in 5% CO2 as previously described . The non-adherent population was removed after 72 hours, and the adherent cells were washed with fresh media and cultured for 7 days. The resulting adherent cells were harvested by incubating with 0.25% trypsin (Invitrogen Corporation) followed by gentle scraping. By means of negative selection via immunomagnetic column (Miltenyi Biotec, Auburn, CA, USA), cells negative for CD11b (eBioscience, San Diego, CA, USA) and CD45 (eBioscience) were placed back into culture. A homogenous cell phenotype was confirmed on the basis of the expression of CD29, CD44, and Sca1 and the absence of hematopoietic (CD45, CD14, and CD11b) markers. Prior to use, cells had been passaged from one to four times.
Human decidua parietalis placenta stem cells
All studies were approved by the Institutional Review Board of the University of Illinois. hdpPSCs were isolated from the decidua parietalis dissected from placental membranes after normal vaginal delivery at term, as previously described in detail . Human placenta tissue was obtained from the Human Female Reproductive Tissue bank in the Center for Women's Health and Reproduction at the University of Illinois at Chicago. Cells were cultured in RPMI-1640 medium supplemented with 10% heat-inactivated and charcoal-stripped fetal bovine serum, 0.1 mM sodium pyruvate, and 1% penicillin/streptomycin. At confluence, cells were trypsinized, propagated, and used for experiments in passage numbers three to five.
sAPPα (Sigma-Aldrich) was used at 10 nM concentrations unless otherwise indicated (dissolved in phosphate-buffered saline, or PBS).
Neurosphere media was conditioned by plating 3 × 105 NPCs in each well of a 12-well plate in 500 μL of complete media. After 1 hour, media was removed and spun at 1,000g for 10 minutes to remove any cells or debris. For depletion of sAPP, conditioned media was precleared with protein A-agarose beads (Pierce, Rockford, IL, USA) and then incubated overnight at 4°C with 22C11 antibodies against the N-terminus of APP or IgG antibodies (Millipore Corporation, Billerica, MA, USA) as a control. Protein A-agarose beads were added for 30 minutes, the mixture was spun at 4,000 revolutions per minute (rpm) for 3 minutes, and the supernatant was used as depleted media. Regular conditioned media was subjected to the same process without antibody incubation as a control. All media was filtered through a 0.22-mm filter prior to addition.
Detection of sAPP
For the detection of soluble APP from brain lysates, protein was extracted in immunoprecipitation buffer containing 150 mM NaCl, 50 mM Tris-Cl, 5 mM ethylenediaminetetraacetic acid (EDTA), 1% Triton-X 100, 0.5% sodium deoxycholate, protease inhibitor cocktail, and 250 μM phenylmethylsulfonyl fluoride (PMSF). To remove full-length APP, protein samples were immunodepleted by using 369 antibodies against the C-terminus of APP (a gift from Sangram S Sisodia, The University of Chicago). Briefly, samples were precleared with 50 μL of immobilized protein A-agarose beads (Pierce) at 4°C for 30 minutes. Samples were centrifuged at 4,000 rpm for 3 minutes, and the pellet was discarded. To the supernatant, 5 μL of 369 antibody was added and incubated overnight at 4°C. The next morning, 50 μL of immobilized protein A was again added for 30 minutes at 4°C and spun at 4,000 rpm for 3 minutes. The pellet contains the full-length APP-369 antibody complex, and the supernatant was probed for sAPP by using 22C11 antibodies raised against the N-terminus of APP (Millipore Corporation).
Neurosphere formation (clonogenic) assay
Briefly, neurospheres were singly dissociated by mechanical dissociation and plated at 1,000 cells per well onto 96-well plates. For matrix-metalloproteinase (MMP) inhibitor experiments, cells were then treated with the indicated molar concentration of GM6001 or GM6001 negative control (Millipore Corporation) and the indicated molar concentrations of sAPP or conditioned media. If not otherwise indicated, 1 μM GM6001 and negative control inactive inhibitor (NC) were used. Cells were treated every 72 hours for 10 days. After 10 days in culture, neurospheres were counted under an inverted light microscope, and the average neurosphere diameter was calculated from 25 randomly assigned squares of the grid by using a Zeiss AX10 microscope (Carl Zeiss Ltd., Hertfordshire, UK) and StereoInvestigator software (MBF Bioscience, Williston, VT, USA). After sphere size determination, cells were singly dissociated with a p200 pipette and counted with a hemocytometer. The remaining cells were placed onto Matrigel-coated chamber slides for 30 minutes and then fixed in 4% paraformaldehyde for 30 minutes for immunocytochemistry. Briefly, cells were washed four times in Tris-buffered saline (TBS) and then placed into blocking solution (5% normal donkey serum, 0.25% Triton-X 100 in TBS) for 30 minutes at room temperature. Next, cells were incubated in primary antibodies-mouse anti-nestin (1:100; Millipore Corporation) and goat anti-Sox2 (1:200; Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA)-in TBS containing 0.25% Triton-X 100 for 1 hour at room temperature. After primary antibodies, cells were again incubated in blocking solution for 30 minutes at room temperature before secondary antibody incubation-anti-goat cy5 (1:250; Jackson ImmunoResearch Laboratories, Inc., West Grove, PA, USA) and anti-mouse cy3 (1:500; Jackson ImmunoResearch Laboratories, Inc.)-in TBS with 0.25% Triton-X 100 for 30 minutes at room temperature in the dark. Cells were then washed four times in TBS and incubated for 5 minutes with DAPI (4'-6-diamidino-2-phenylindole) (1:50,000; Invitrogen Corporation) at room temperature in the dark. Cells were then washed three times and mounted with polyvinyl alcohol-DABCO mounting solution. Cell counts were made by means of StereoInvestigator software version 8 (MBF Bioscience).
Mesenchymal and placental cell proliferation experiments
MSC or hdPSC were trypsinized for 5 to 10 minutes with 0.05% trypsin, collected after trypsin inactivation, and spun at 500g for 5 minutes. Pellets were then dissociated and plated at 1,000 cells per well in 96-well plates. Cells were then treated with the indicated molar concentration of GM6001 or GM6001 negative control (Millipore Corporation) and the indicated molar concentrations of sAPP. After 3 days in culture, cells were trypsinized for 5 to 10 minutes, spun, and counted with a hemocytometer.
Brain tissue for biochemistry and immunohistochemistry
Experiments using animals were performed according to guidelines of the National Institutes of Health and the University of Illinois at Chicago Institutional Animal Care and Use Committee. The APP knockout [APP(-/-)] model has been described previously [23, 24]. Briefly, the authors generated the mice through homologous recombination in embryonic stem cells. Mice heterozygous for APP expression were cross-mated and APP(+/+) (APP wild-type), APP(+/-), and APP(-/-) resulted from this breeding. Our colony is maintained via group housing (fewer than five mice per cage) in a barrier facility under a 14:10 light/dark cycle with free access to food and water. Animal care and procedures were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Brain tissue processing
For in vivo immunohistochemical staining, male APP(+/+) mice from 3 to 5 months old were used. All mice were anesthetized with a mixture of ketamine and xylazine and transcardially perfused with 100 mL of ice-cold PBS. The brains were then removed and halved in the sagittal plane. The left half was immediately placed into 4% paraformaldehyde on ice. From the right half of the brain, the following regions were dissected for biochemical analysis and immediately placed into Eppendorf tubes on dry ice: SVZ, hippocampus, olfactory bulb, frontal cortex, and cerebellum.
Left hemibrains from PBS-perfused mice were post-fixed in 4% paraformaldehyde for 3 days and stored in 30% sucrose at 4°C. Hemibrains were sectioned sagittally at 50 μm by using a microtome and placed into cryopreservent (47.6% PBS, 28.57% ethylene glycol, and 25% glycerin vol/vol). Sections were blocked by using a solution containing 0.25% vol/vol Triton-X 100 (Sigma-Aldrich) and 5% vol/vol Normal Donkey Serum (Jackson ImmunoResearch Laboratories, Inc.) in TBS. The following antibodies were used: Dlx-2 (1:200; Millipore Corporation), nestin (1:100; Millipore Corporation), Sox2 (1:100; Santa Cruz Biotechnology, Inc.), ADAM10 (1:200; Millipore Corporation), and APP (22C11; Millipore Corporation and A8717; Sigma-Aldrich). Floating sections were incubated in primary antibodies for 72 hours at 4°C before continuing with blocking, biotin conjugation (Jackson ImmunoResearch Laboratories, Inc.), and secondary antibody incubation (cy2 Streptavidin, anti-mouse cy3, anti-goat cy5, and anti-rabbit cy5; Jackson ImmunoResearch Laboratories, Inc.).
Protein extraction from brain tissue was performed in lysis buffer containing 1X TNE, 50 mM Tris, 150 mM NaCl, 5 mM EDTA, protease inhibitor cocktail (Sigma-Aldrich), and 100 mM PMSF. Quantification of protein was performed by using the bicinchoninic acid (BCA) method (Pierce), and equal amounts of protein were subjected to direct immunoblotting. For the extraction of protein from neurosphere, mesenchymal, and Human decidua parietalis placenta stem cells cultures, a lysis buffer containing 150 mM NaCl, 50 mM Tris-Cl, 5 mM EDTA, 1% Triton-X 100, 0.5% sodium deoxycholate, protease inhibitor cocktail, and 250 μM PMSF was used. For quantification, at least three cultures were used.
Erk and Akt signaling
To assay phosphorylation of Erk and Akt, neurospheres were singly dissociated and plated at 5 × 105 cells per well in a six-well plate in Earle's balanced salt solution (Sigma-Aldrich) and treated immediately with 1 μM GM6001 or GM6001 negative control. After 1-hour incubation at 37°C, one of the GM6001-treated groups was subsequently treated with 10 nM recombinant sAPPα (Sigma-Aldrich) for 15 minutes before all groups were lysed in ROLB buffer: 10 mM HEPES, pH 7.4, 0.5% Triton X-100, 80 mM β-glycerophosphate, 50 mM sodium fluoride, 2 mM sodium orthovanadate, 100 nM staurosporine, 100 nM K252a, 50 nM okadaic acid, 50 nM microcystin, mammalian protease inhibitor cocktail (Sigma-Aldrich), and phosphatase inhibitor cocktail II (Calbiochem, now part of EMD Biosciences, Inc., San Diego, CA, USA) in water. After lysis, protein quantification was performed by using the BCA method (Pierce), and equal amounts of protein were run on Tris-glycine gels and transferred to nitrocellulose membranes. For blocking and antibodies, we employed a solution of 0.05% vol/vol Tween, 10% wt/vol milk, and 0.1% wt/vol BSA (Sigma-Aldrich) in TBS. The following antibodies were used: pErk (1:500; Santa Cruz Biotechnology, Inc.), Erk (1:1,000; Santa Cruz Biotechnology, Inc.), pAkt (1:1,000; Cell Signaling Technology, Inc., Danvers, MA, USA), and Akt (1:500; Cell Signaling Technology, Inc.). (N = 3 for Erk and Akt Western blot quantification.)
sAPPα rescues proliferation of neural progenitor cells after treatment with a matrix-metalloproteinase and ADAM inhibitor
sAPPα regulates neural progenitor cell proliferation in an EGF- and bFGF-independent manner
sAPPα regulates the proliferation of adult stem cells of non-neural origin
High levels of sAPP are expressed in the subventricular zone of adult mice
To determine whether the NSC and NPC populations that express APP resemble those observed in vitro in neurosphere culture, we double-stained brain sections of adult mice with antibodies raised against APP, Sox2, nestin, and Dlx-2, the last of which is a homeobox protein expressed in transit-amplifying C cells of the adult SVZ . APP expression colocalized with all three markers, suggesting that APP is expressed in NSCs and transit-amplifying NPCs in the adult SVZ (Figure 6e).
ADAM10 is expressed in the subventricular zone and hippocampus of adult mice
sAPP regulates extracellular signal-regulated kinase activity
During the last two decades, there has been much interest in unraveling the physiological role of APP, its metabolites, and the physiological significance of its multiple metabolic pathways. Here, we show that sAPPα, a product of APP cleavage by α-secretase, is a proliferation factor of NPCs in the adult brain, MSCs, and hdpPSCs. This suggests an important role for sAPPα as a proliferation factor of different stem cell populations in the adult. The diversity of stem cells that respond to sAPPα as a proliferation factor leads us to suggest that sAPPα exerts its effect on a wide range of stem cell populations. NPCs used in this study were derived from the adult mouse brain. MSCs were isolated from the bone marrow of adult mice, and hdpPSCs were isolated from the decidua parietalis dissected from placental membranes. All stem cell populations have self-renewal capability. Whereas NPCs are capable of differentiating into neurons or glia only, MSCs exhibit multilineage potential into many mesodermal cell types and possibly into endodermal and ectodermal cells as well (reviewed in ). hdpPSCs are of human fetal origin and are thought to exhibit multilineage potential .
These results provide functional significance for the fact that APP is ubiquitously expressed and is highly conserved in evolution (reviewed in ). We show that sAPPα is a potent factor that can recover proliferation of these stem cell populations after treatment with an MMP inhibitor. The importance of our observations is supported by studies reporting that the expression of sAPPα can rescue behavioral and physiological deficits of APP knockout mice, such as growth and brain weight deficits, agenesis of the corpus callosum, and impaired spatial learning associated with impaired long-term potentiation, suggesting that sAPPα is sufficient for the execution of APP function compromised in its absence [35, 36].
APLP1 and APLP2 have substantial homology to APP, both within the ectodomain and particularly within the cytoplasmic tail . Support for functional redundancy between APLP2 and APP/APLP1 comes from studies of combined knockouts . Cleavage of APLP1 and APLP2 by α-secretase yields sAPLPα of unknown function, which may play a role similar to that of sAPPα in NPC and other stem cell populations. As we cannot exclude a potential functional redundancy between sAPPα and sAPLP2α, we avoid a potential compensatory effect of sAPLPα in the present study by using the GM6001 MMP inhibitor that inhibits APLP1,2 cleavage by α-secretase as well. Expression levels of sAPPα were particularly high in the SVZ. That may suggest that NPC proliferation is differentially regulated in the two neurogenic microenvironments in the adult brain  (and that sAPPα plays an important role in the SVZ specifically) or simply reflect the fact that the neurogenic population is larger in the SVZ. Expression levels of the α-secretase, ADAM10, are significantly higher in the SVZ compared with the dentate gyrus or to the SVZ of APP(-/-), suggesting a correlation between α-secretase and sAPPα in the neurogenic regions. Like in the case of sAPPα, the higher level of ADAM10 expression in the SVZ may be a reflection of the greater population of NSCs and NPCs residing in the SVZ. While GM6001 inhibited α-secretase activity in NPCs, MSCs, and hdpPSCs, we cannot exclude the possibility that the identity of the dominant α-secretase in each one of these stem cell populations is different, representing a different member of the ADAM family, each of which is differentially expressed in a tissue- or niche-specific manner.
Finally, we provide an insight into the mechanism by which sAPPα exerts its proliferative effect in NPCs. We show that it acts in an EGF- and bFGF-independent manner. It has been suggested that, because of the presence of a heparin-binding domain adjacent to the putative growth factor domain in APP  and the presence of sAPP-binding sites on EGF-responsive NPCs , signaling of sAPP may involve other factors (such as EGF) which also can interact with heparin. Our results suggest that any interaction of sAPPα and EGF or bFGF is not necessary for the proliferation-related functions of the molecule. Furthermore, we show that sAPPα signaling is associated with ERK/MAP kinase signaling. Increased phosphorylation of ERK is indicative of signaling through the MAP kinase pathway. In NPCs, ERK signaling is crucial for carbachol-induced increases in DNA synthesis , inhibiting MAP kinase signaling decreases BrdU incorporation after heparin-binding EGF activation , and MEK 1 and 2 inhibitor, U0126, inhibits proliferation after hypoxia/reoxygenation . All of these factors point to ERK/MAP kinase as a critical pathway in the proliferation of NPCs. Another critical pathway involved in proliferation of NPCs, Akt [41–44], was not activated by sAPPα in vitro. Previous investigations using pharmaceutical inhibitors of either the ERK/MAP kinase pathway or the Akt/PI3-K pathway suggest that PI3-K inhibition results in both self-renewal deficits and proliferation decline whereas MAP-kinase inhibition affected proliferation only .
In summary, we provide evidence that, by signaling through MAP kinase pathways, the evolutionarily conserved sAPPα regulates the proliferation of adult stem cells originating from different germ layers. Future studies should determine whether a reduction in α-secretase activity or in sAPPα production or in both contributes to the aging of these stem cell populations.
a disintegrin and metalloproteinase
amyloid precursor protein
basic fibroblast growth factor
bovine serum albumin
Dulbecco's modified Eagle's medium/F12
epidermal growth factor
extracellular signal-regulated kinase
Human decidua parietalis placenta stem cells
mesenchymal stem cell
negative control inactive inhibitor
neural progenitor cell
neural stem cell
revolutions per minute
soluble amyloid precursor protein alpha
subgranular layer of the dentate gyrus
sortilin-related receptor with type-A repeats
This study was supported by NIA AG033570 (OL), an Alzheimer's Association Young Investigator Award (OL), an Illinois Department of Public Health ADRF award (OL), and the Brain Research Foundation (OL).
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