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:
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
Copyright © 2013 Christopher P. Sullivan et al. This is an open access article distributed under the Creative Commons Attribution
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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