Phosphorylated low-density lipoprotein receptor-related protein 6 is prevalent in hippocampal progen

Vol.2, No.4, 126-131 (2013) Advances in Alzheimer’s Disease

http://dx.doi.org/10.4236/aad.2013.24017

Phosphorylated low-density lipoprotein

receptor-related protein 6 is prevalent in

hippocampal progenitor cells and circuits

of aged human hippocampus

Christopher P. Sullivan1,2*, Rosemary Elliott-Bryant1, Anish Kanesa-Thasan1,

Ann C. McKee1,2,3, Richard E. Fine1,2,4, John M. Wells1,2, Peter J. Morin1,2,4

1Geriatric Research Education and Clinical Center, Bedford VA Hospital, Bedford, USA;

*Corresponding Author: sullivan95@gmail.com

2Department of Neurology, Boston University School of Medicine, Boston, USA

3Department of Pathology, Boston University School of Medicine, Boston, USA

4Department of Biochemistry, Boston University School of Medicine, Boston, USA

Received 29 May 2013; revised 5 July 2013; accepted 18 July 2013

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Wnt signaling has been implicated in Alzhei-

mer’ s disease (AD) pathogenesis, but no studies

have described Wnt signaling in aging brain.

Phosphorylation of the Wnt co-receptor, low-

density lipoprotein receptor-related protein 6

(Lrp6), is a sensitive indicator of Wnt ligand-

receptor interaction and canonic al Wnt signaling.

We report that in aged human temporal lobe, the

phospho-Lrp6 (pLrp6) epitope localizes to neu-

rons in the entorhinal cortex (EC), the dentate

gyrus (DG), and the hippocampal formation, es-

pecially in the CA3 field. Activated Lrp6 is de-

tected in neuronal soma and in neuronal proc-

esses, particularly in the mossy fiber terminals

in the stratum lucidum of CA3. These three re-

gions and their connectivity represent the af-

ferent arm of the major hippocampal circuit. In

the DG, cells positive for pLrp6 include Type 1

and Type 2 hippocampal progenitor cells. Over-

all, these data indicate regional Wnt receptor

activation in the human hippocampus that is

most prominent in the cells comprising the af-

ferent arm of the major hippocampal circuit that

is associated with learning and memory func-

tions. These findings are consistent with data

from rodent studies which suggest an important

role for Wnt s in adult neurogenesis in the human

DG. We speculate that Wnt signaling may be an

activity-dependent trophic influence in the hip-

pocampus.

Keywords: Wnt; LRP6; Hippocampus; CA3;

Neurogenesis; Alzheimer’s

1. INTRODUCTION

Limited human data suggest that adult neurogenesis in

the human hippocampus may differ substantially from

rodent models. Doublecortin-expressing cells in human

DG diminish in number with advancing age through the

tenth decade of life [1] and, unlike rodent models, may

be increased in Alzheimer’s disease patients compared to

age-matched controls [2,3]. One feature of adult neuro-

genesis that is likely to be preserved across mammalian

species is the role of regulatory mechanisms, including

Wnt signaling. The neurodevelopment [4,5] and mainte-

nance [6] of the mammalian mesial temporal lobe are de-

pendent on Wnt signaling. Canonical Wnt signaling is

thought to be critical for multiple cell fate decisions in both

embryonic and adult neurogenesis [7]. These functions of

Wnts in adult neurogenesis have been demonstrated using

molecular techniques that cannot be applied in human brain.

Recent advances in studies of Wnt signal transduction

have identified a unique and sensitive marker of canoni-

cal Wnt signaling. Upon Wnt binding to the Wnt receptor

complex, the Wnt coreceptor, Lrp6, is phosphorylated at

five conserved PPPSPxS motifs on its short intracellular

domain (ICD) [8]. The detection of this phosphoepitope

C. P Sullivan et al. / Advances in Alzheimer’s Disease 2 (2013) 126-13 1

127

has been shown to be a highly sensitive indicator of ac-

tive canonical Wnt signaling that correlates tightly with

Super8Topflash (Tcf4) luciferase Wnt-reporter activity in

tissue culture models [9].

Here we report that Wnt receptor activation, as indi-

cated by the presence of the pLrp6 epitope, is abundant

in cells in the CA3 field, DG and EC of adult human

hippocampus. These cells comprise the afferent arm of

the major circuit of the hippocampus that is critical for

memory and learning [10]. We also find that pLrp6-

positive cells in the aged human dentate gyrus bear mar-

kers of hippocampal progenitor cells and mature neurons.

These findings are consistent with rodent data and sug-

gest that Wnt signaling is active in neurons in the adult

human hippocampus.

2. MATERIALS AND METHODS

2.1. Subjects and Tissue Preparation

Human brain tissue used in this study was obtained

from the Department of Veteran Affairs VISN1 Neuro-

pathology Center, the Framingham Heart Study (FHS),

and the Boston University Alzheimer’s Disease Center

(ADC). Hippocampal tissue sections from twenty adults

over the age of 62 (average age of 81) were evaluated for

this study. Brain specimens were fixed in 4% PLP (pH

7.4). After fixation, hippocampus tissue was dehydrated

and paraffin-embedded. Postmortem interval (PMI) for

brain fixation ranged between 1.5 hours and 24 hours

among specimens with an average PMI of 6.8 hours.

2.2 Western Blot

HEK 293 cells were grown on 6-well tissue culture-

treated dishes (BD Biosciences) and treated with normal

or Wnt-conditioned media for various time periods. Cell

lysates were collected in RIPA buffer (Pierce) in the

presence of phosphatase inhibitors (HALT cocktail—

Pierce). Proteins were separated by polyacrylamide gel

electrophoresis and transferred to polyvinylidene fluoride

membranes. Membranes were blocked in SuperBlock

(Pierce) before incubation with rabbit anti-pLrp6 anti-

body (Cell Signaling Technologies) overnight. After wash-

ing, membranes were treated with HRP-tagged donkey

anti-rabbit secondary antibody (Vector Labs) and visual-

ized by chemiluminescence (Pierce).

2.3. Immunocytochemistry

HEK 293 cells were grown on chamber slides (BD

Biosciences) and treated with normal or Wnt-conditioned

media for 12 hours. Cells were washed with PBS and

fixed in PBS with 4% paraformaldehyde for 10 minutes.

Cells were permeabilized with PBS containing 0.1%

TX-100 (BioRad) for 3 minutes, and blocked in PBS

containing 5% normal goat serum before incubating with

primary antibodies overnight at 4˚C, followed by treat-

ment with fluorescently-labeled secondary antibodies (In-

vitrogen) as previously described [11].

2.4. Immunohistochemistry

5 μm paraffin-embedded formalin-fixed human hip-

pocampal sections were deparaffinized and rehydrated

with distilled water. Sections were blocked in Super-

Block reagent (ScyTek) with 5% serum derived from the

species used to raise the secondary antibody. Detection

of pLrp6 in tissue sections was carried out using a

Ser1490 phosphorylation site-specific primary antibody

(Cell Signaling Technologies). For brightfield micros-

copy, detection of pLrp6-bound primary antibodies was

carried out with horse radish peroxidase (HRP)-conju-

gated secondary antibodies, exposed by enzymatic proc-

essing of diaminobenzidine (DAB). Fluorescence confo-

cal microscopy (Leica SP5) was used as previously de-

scribed [12] to assess colocalization of pLrp6 with pri-

mary antibodies bound to NeuN, Sox2, and GFAP (Santa

Cruz Biotechnology). Secondary antibodies conjugated

with Alexafluor 488, 555 or 633 dyes (Life Technologies)

were used to detect bound primary antibodies for fluo-

rescence imaging. To reduce background fluorescence,

slides were immersed in lipofuscin-reducing solution [5

mM CuSO4 in 50 mM ammonium acetate buffer (pH 5)]

for 10 minutes before mounting.

3. RESULTS

3.1. pLrp6 Epitope Is Responsive to Wnt3A

Phosphorylation of Lrp6 occurs in response to the

binding of Wnt ligand to the Wnt receptor complex [8].

The specificity of this epitope as a marker of active Wnt

signaling in human cells is well established [13] and is

demonstrated here by exposing HEK 293 cells to Wnt3A

or control conditioned medium. Detection of pLrp6 at

various time points by western blot (Figure 1(a)) and

immunocytochemistry (Figure 1(b)) was possible only

in cells exposed to Wnt3A conditioned medium.

3.2. pLrp6 in Human Hippocampus

While anti-pLrp6 antibodies have been used to detect

Wnt activity in lysates and cultured cells, the distribution

of pLrp6 in human tissues has not been characterized

histologically. In the human hippocampus, previous

studies have characterized Wnt signaling at the level of

Wnt expression and Wnt-dependent gene expression,

using in situ hybridization and immunostaining to detect

Wnt-dependent transcripts and proteins [1,6]. To detect

Wnt signaling in the adult hippocampus at the level of

Wnt receptor activation, immunostaining to detect pLrp6

C. P Sullivan et al. / Advances in Alzheimer’s Disease 2 (2013) 126-13 1

128

Figure 1. Lrp6 is phosphorylated in re-

sponse to Wnt treatment. HEK 293 cells

were treated with Wnt-conditioned me-

dia for the indicated times before analy-

sis by Western blot and ICC. (a) Western

blot analysis using anti-pLrp6 antibody

was carried out on cell lysates harvested

20 mins, 2 hours and 6 hours after Wnt

treatment; (b) Detection of Lrp6 and

pLrp6 by immunofluorescence micros-

copy was carried out on cultured cells

treated overnight with Wnt-conditioned

media. Scale bar equals 10 μm.

was carried out. Phosphorylated Lrp6 is detected in cells

in the hippocampal formation, DG, and EC (Figure 2).

DAB-positive cells (brown) are seen in most cortical

regions but are most prevalent in the EC and in CA3

(bottom panel). In the EC, pLrp6 is seen in large pyra-

midal neurons and some signal is observed in processes

extending from these cells towards the hippocampus. In

many cases, a large number of these processes are seen

crossing the hippocampal fissure in line with the per-

forant pathway en route from the EC to the DG and CA3.

In some cases, pLrp6 was also seen in neurons in the

parasubiculum, and, much less frequently, in the subicu-

lum. Cytoarchitectonic distinction of EC from parasubi-

culum was difficult in these aged brains, but the location

within the parahippocampal gyrus is most consistent with

neuronal staining in the EC. DAB detection was dimin-

ished in control experiments where the antibody solu-

tion was preincubated with an excess of pLrp6 block-

ing peptide (21st Century Biochemicals) or where a

normal rabbit IgG was used in place of anti-pLrp6

(Figure 3).

In the hippocampal formation, many pLrp6-positive

neurons were observed throughout the CA fields. The

CA3 field; however, contained by far the highest density

of DAB-positive pyramidal neurons. As in the EC, many

pLrp6-enriched neuronal processes were observed in the

Figure 2. Cells of the hippocampal DG, CA3 and EC

harbor pLrp6. Adult human tissue sections were im-

munostained using anti-pLrp6 antibody and visualized

by DAB treatment (brown color). A cross section of

the hippocampus is pictured (c) along with enlarged

regions highlighting the mossy fibers of CA3 (a) and

granule cells of the DG (b). DG—dentate gyrus; EC—

entorhinal cortex; GCL—granule cell layer; SGZ—

subgranular zone. Scale bars equal 200 μm.

Figure 3. Antigen detection is diminished under con-

trol conditions. Adult human tissue sections were

immunostained using either ((A) and (D)) anti-pLrp6

antibody, ((B) and (E)) anti-pLrp6 antibody preincu-

bated with a 10-molar excess of a peptide corre-

sponding to the phosphorylated epitope of Lrp6 (21st

Century Biochemicals) or ((C) and (F)) with a equal

concentration of normal rabbit IgG (Vector Labs)

used in place of anti-pLrp6. Bound antibodies were

visualized using DAB detection. Scale bar equals 75

μm.

CA3 field. In addition to processes in the CA3 field

proper, pLrp6 was invariably observed in the stratum ra-

diatum (upper left panel) of CA3, an area were the den-

dritic fields of these cells receive mossy fiber input from

the DG.

In the DG, diffuse pLrp6 signal was consistently ob-

C. P Sullivan et al. / Advances in Alzheimer’s Disease 2 (2013) 126-13 1 129

served in the molecular layer. In the granular cell layer

(GCL), pLrp6 was found in a variable and patchy distri-

bution with the highest prevalence found near the tips of

the superior and inferior blades. In the most densely

stained regions, approximately 10% - 20% of the cells

stained positively for pLrp6 and exhibited variable mor-

phology. Near the subgranular zone (SGZ), pLrp6-posi-

tive cells were small with minimal cytoplasm. Cells deep-

er in the DG and approaching the molecular layer exhib-

ited the morphology characteristic of mature granule

cells, with thick proximal dendritic shafts enriched with

pLrp6.

3.3. Neuronal Identity of pLrp6-Positive

Cells

To determine the identity of the pLrp6-positive cells,

the co-localization of pLrp6 with established markers of

neurons and neural precursors was evaluated. Adult hip-

pocampal tissue sections were subjected to double fluo-

rescence immunostaining for pLrp6 and the neuronal

marker NeuN. All pLrp6-positive cells in the EC and

CA3, as well as most of the cells in the DG, had a dis-

tinctive neuronal morphology. Fluorescence imaging of

DG cells (Figure 4(A)) demonstrated that virtually all of

the pLrp6-positive cell bodies co-localized with NeuN

(red) and bright pLrp6 signal (green) was observed in

both the soma and proximal processes. Additionally, we

tested the hypothesis that pLrp6 might be associated with

neural precursor cells in the DG, a known neurogenic

zone [14]. Colocalization of pLrp6 (green) and Sox2

(red), a transcription factor expressed by hippocampal

progenitor cells, was examined by laser scanning confo-

cal microscopy in the DG (Figure 4(B)). While many of

the Sox2-positive cells in the DG did not express pLrp6,

many of the pLrp6-positive cells also expressed Sox2.

Current evidence suggests that two types of hippo-

campal progenitor cells exist in the DG, Type 1 and Type

2 [15]. In addition to morphological differences, these

cell types can be characterized by whether or not they

express glial fibrillary acidic protein (GFAP) and hence

become mature astrocytes. While both cell types express

Sox2, Type 2 progenitors also express GFAP and Type 1

cells do not. To determine whether pLrp6-positive cells

could be Type 1 or Type 2, triple immunofluorescent

staining was carried out on human hippocampal tissue

sections to colocalize pLrp6 with both Sox2 and GFAP.

Lrp6 phosphorylation was observed in both Type 1 (Fig-

ure 4(C-bottom)) and Type 2 (Figure 4(C-top)) neural

progenitors. Thus, our data are suggestive of Wnt recap-

tor activation in both Type 1 and Type 2 progenitor cells,

a result that is consistent with observations of cell prolif-

eration in human DG [14,15].

Figure 4. Wnt-activated cells in the human

DG colocalize with neuronal and stem cell

specific markers. (A) DG cells positive for

pLrp6 (green) colocalize with the neuronal

marker NeuN (red); (B) A subset of cells

expressing Sox2 (red) also contain pLrp6

(green) (areas of colocalization appear in

yellow in the merged image); (C-top) A sub-

set of cells expressing pLrp6 (green) and

Sox2 (red) also express GFAP (blue) while

others (C-bottom) do not. Scale bars equal

50 μm.

4. DISCUSSION

In this study, we demonstrate that pLrp6 is present in

post mortem aged human brain and we report three novel

findings. These results establish a method for studying

Wnt signaling activity in situ, demonstrate regional Wnt

signaling within the medial temporal lobe structures, and

implicate Wnt signaling in adult neurogenesis in human

brain.

Our data suggest that Wnt signaling in the human

hippocampus is mostly active in neurons. In the central

nervous system (CNS), Wnt signaling has been found in

neurons [16], astrocytes in response to brain injury [17],

and endothelial cells [18]. Most of the pLrp6-positive

cells bodies we identified in EC and CA3 expressed

NeuN and most exhibit a distinctly neuronal morphology

(Figures 2 and 4). Immunoreactivity was observed in

neuronal soma and in straight-shaft processes that con-

form to established tracts, suggesting a neuronal local-

ization. In the CA3 region, pLrp6 signal may also be

associated with synaptic structures. DAB signal in the

mossy fibers is somewhat diffuse, and some synaptic

bouton-associated immunoreactivity cannot be excluded.

Some of the regions of intense cell staining might in-

clude endothelial cells, but the morphological features of

pLrp6-positive cells are most consistent overall with

neuronal cells, and no distinctive features of glial or en-

dothelial cells have been identified.

In the DG, pLrp6-positive cells exhibit a spectrum of

C. P Sullivan et al. / Advances in Alzheimer’s Disease 2 (2013) 126-13 1

130

morphologies. Within the GCL, small cells with limited

cytoplasm are often seen near the SGZ, while large cells

with a distinctly neuronal morphology (including proc-

esses) are seen throughout the DG and often are closer to

the molecular layer. Frequently, small pLrp6-positive

cells are found in small clusters, suggesting a common

lineage. Of the pLrp6-positive cells observed in the DG,

many express Sox2, and a subset express both Sox2 and

GFAP. These findings suggest that Wnt receptor activa-

tion is present in hippocampal progenitor cells. Current

data from rodents support a role for canonical Wnt sig-

naling in multiple stages of neurogenesis, including asym-

metric division of radial glial cells and expansion of in-

termediate precursor cell populations [6]. Our human da-

ta are consistent with these findings.

We cannot, however, exclude the possibility that ca-

nonical Wnt signaling may be active in these cells due to

synaptic activity. Recent studies support a role for activ-

ity-dependent Wnt signaling in synaptic remodeling [19],

including experiential synaptic remodeling in the den-

drites of CA3 neurons [20]. While preliminary experi-

ments did not identify activity-dependent epitopes in

these cells (not shown), we are continuing to explore this

hypothesis. The presence of the pLrp6 in some mature

DG granule cells could also indicate that the activated

Wnt receptor is retrogradely transported. Support for

such a model stems from reports of trans-synaptic activ-

ity of wingless (Wg) at the Drosphila neuromuscular

junction where pre-synaptic Wnt ligand secretion is

tightly coupled, through a mechanism involving exosome

secretion [21], to retrograde transport of post-synaptic

Wg receptor (DFr2) [22]. This explanation is consistent

with the appearance of pLrp6 in neuronal processes in

the EC, DG, and CA3. Finally, these data do not exclude

the possibility of cell-autonomous regulation of receptor

activation by a ubiquitous Wnt signal in the extra cellular

matrix. Further studies will be necessary to determine the

mechanisms and function of Wnt signaling in human

neurons.

The regional distribution of pLrp6 coincides with the

afferent arm of the major hippocampal circuit that has

been implicated in learning and memory [10]. This cir-

cuit includes the EC, the DG and the CA3 field of the

hippocampal formation. Our data show that mature pLrp6-

positive neurons are found in each of these regions at a

prevalence that exceeds surrounding regions. We also

found pLrp6 in neuronal processes, including in the per-

forant pathway, mossy fibers, and the molecular layer of

the DG. These fibers comprise the major tracts linking

the EC to the CA3. In contrast, less pLrp6 immunoreac-

tivity is seen in the efferent arc of this circuit: the

Schaffer collaterals, CA1, and subiculum. It is important

to emphasize that there is some pLrp6 signal in CA1, but

much less than in CA3. The CA1 signal may reflect EC

neurons projecting directly to CA1. The significance of

relatively robust Wnt signaling in hippocampal circuitry

that is well known for plasticity is not immediately clear.

We are inclined to interpret these findings as supporting

a role for Wnt signaling in synaptic remodeling. One

caveat relates to studies of “activity-dependent” findings

in post mortem tissue. In this setting, activity-dependent

signaling could be related to neural activity at or near the

time of death and/or be related to unique circuits within

the EC-DG-CA3 circuit. Such data may be distorted in

human autopsy tissue due to the post mortem interval

measured in hours. Further experiments in mouse brain

will be necessary to investigate activity-dependent Wnt

signaling in the hippocampus. These studies have poten-

tial implications for AD [23] where deranged Wnt sig-

naling in the aged hippocampus could be associated with

synaptic injury and spread to interconnected brain re-

gions. The distribution of pLrp6 that we observe corre-

sponds to that of neuronal circuits is known to be injured

early in the disease process and that are associated with

amnestic symptoms that characterize early age-related

memory deficits [24]. Additional studies aimed at evalu-

ating Wnt signaling activity in AD brain will be neces-

sary to establish the significance of these neuropatho-

logical findings.

5. ACKNOWLEDGEMENTS

This material is based upon work supported by the Department of

Veterans Affairs, Veterans Health Administration, Office of Research

and Development, Biomedical Laboratory Research and Development.

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the National Academy of Sciences of the United States of

America, 108, 8873-8878.

http://dx.doi.org/10.1073/pnas.1101567108

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