Alzheimer’s disease (AD) is the most abundant form of dementia worldwide and elderly people are prone
to this disease. Until now, no such therapeutic intervention has been identified to curb it. Wnt signaling
being a major regulator of systemic homeostasis, plays a significant role in the disease response. Wnt
signaling pathway is intrinsically associated with the regulation of synaptic plasticity, microglial activation
and maintenance of blood brain barrier (BBB). In spite of these all-round executions, there is a lack of
detailed study to present an opinion about the importance of this signaling cascade in AD. In this review
we will uphold the major queries related to the disease which can be elucidated by Wnt signaling pathway.
Alzheimer’s disease is one of the most prevalent
neurodegenerative diseases in the world which mostly appears
with aging [1,2]. Neuronal death, followed by cognitive decline and
memory loss serve as an important outcome of the disease [3]. The
Central Nervous System (CNS) comprises different cell types, mainly
neurons and glia (Astrocytes, Microglia, Oligodendrocytes). Glial
cells provide appropriate metabolic support to the neurons for their
proper functioning and helps to maintain a stable bioenergetics for
proper neuronal transmission [4,5]. Nonetheless, different neuronal
type in different region of the brain also regulate the function of the
glial cells in a spatio-temporal manner [6]. This crosstalk between
neuron and glia is regulated by a multitude of signaling processes. Wnt
signaling regulate the proliferation and differentiation of neuronal
stem cells (NSC) and is an integral part of neurogenesis and neuronal
function [7,8]. Wnt ligands also serve as important factors for the
activation of the glial cells, which plays a crucial role in neuronal
apoptosis during neurodegeneration [9,10]. Here, we discuss how
the balance of different wnt ligands can affect the homeostasis of
neuron-glia cross-talk, the anomaly of which is a major driving force
of neurodegeneration.
WNT Signaling in Synaptic Transmission and Cognitive
Decline
Wnt family of protein ligand comprises of 19 different secreted
glycoproteins which are conserved across different mammalian
species [11,12]. Although they are majorly classified in two
classes canonical and non-canonical, the overlap of the signaling
intermediates and outcome is quite often [13,14]. Several studies have
reported the importance of this signaling in dendritic development,
synaptic transmission, synaptogenesis and in different disorders
[15-18]. Cognition, memory and motor movements are among
several behavioral parameters which is compromised in different
neurodegenerative diseases including AD [19]. Wnt7a/b is known
to play a vital role in the assembly of synaptosomes and thereby
contributes to the synaptic plasticity [20,21]. As reduced synaptic
transmission is one of the early markers of AD [22], the variation in
the level of Wnt7a/b signaling cascade in neurons and the glial cells can be highlighted as an important area of future research. Since, Wnt signaling is known to affect the calcium uptake [23,24], an important
contributor of action potential, there is scope of exploration
in the role of Wnt7a/b in calcium uptake deregulation during
neurodegeneration. Whether Wnt7a/b contributes in microglial
activation and astrocytic metabolic disbalance is not known. Since
ROR1, a well-known receptor for different ligands is also a genetic
risk factor for AD, It will be intriguing to look at the interaction of
different Wnt ligands (Wnt7a/b, Wnt5a, Wnt3a) with ROR1 in cellspecific
context in the diseased brain.
Wnt Signaling in Disease Associated Microglia
Microglia are the immune cells residing in CNS and equipped with
metabolic versatility to patrol in different regions of the brain [25,26].
During host-pathogen interaction, Wnt5a is known to regulate the
uptake and autophagy mediated containment of the pathogens
through alteration of cytoskeletal dynamics in macrophages [27-30].
Since impaired autophagy in neurons and microglia in diseased brain
is very well characterized [31,32], further insight into the status of
Wnt signaling intermediates in different brain cell types can provide
deeper knowledge about the impact of this pathway in AD. Canonical
Wnt3a/β-catenin signaling is known to transcriptionally regulate
the expression of STUB1 [33], an E3 ubiquitin ligase intrinsically
associated with the deposition of misfolded protein aggregates in AD
brain [34,35]. Altogether, Wnt ligands vividly regulate the degradation
machinery of misfolded proteins and cellular components in the
system. Wnt ligands can also regulate the inflammatory state of the
microglia [9]. Dysregulation of these above signaling parameters may
activate the microglia and contribute in their M1 to M2 transition in
CNS. Several lines of evidence suggest that complex Wnt signaling
cascades are closely associated with deposition of cholesterol in
macrophages resulting in aberrantly functioned fatty macrophages at
atherosclerotic lesions [36-38]. On the other hand, cholesterol is also
known to activate different modes of Wnt signaling in a concentration
dependent manner [39]. In AD brains, cholesterol deposition and
excessive lipid droplet formation in microglia has also been recently
reported [40-42]. Taken together, dysfunctional autophagy mediated
degradation machinery and deposition of cholesterol may give rise to
a different class of microglia known as Disease Associated Microglia
(DAM) in the AD brain with distinct transcriptional signatures
[43]. It will be interesting to explore whether Wnt ligands play
similar functions and steers the transformation of microglia from
homeostatic state to proinflammatory DAM state in CNS. WNT/Planar
Cell Polarity (PCP) pathway not only regulates the calcium balance
but also contributes to cytoskeletal alteration and polarity of the cells
[44]. As microglia can migrate in different regions of the brain, it will
be fascinating to explore the role of WNT/PCP pathway in microglial
polarization and their metabolic versatility in disease condition.
WNT Signaling in Astrocytes
Astrocytes are known to be the most important metabolic
lifeline for neurons [45,46]. Astrocytic Wnt signaling is crucial for
maintenance of BBB and protect the neurons [47]. Neurons generate
tons of free fatty acids and different metabolic byproducts during
synaptic transmission but they are not equipped with efficient
cellular machinery to reduce that metabolic stress. Interestingly,
mitochondria in astrocytes are fortified to reduce the Fatty Acid and
lipid stress for neurons due to their efficient ETC (Electron Transport
Chain) complex I assembly and function [48]. Astrocytic activation
and dysfunction are one of the very early manifests of the disease [49],
failing of which leads to neuronal apoptosis. Wnt signaling has not yet
been studied extensively in astrocytic activation. Astrocyte-neuron
lactate shuttle is one of the well-established metabolic pipelines
between neurons and astrocytes. Wnt ligands, being a regulator of
vesicle transport inside the cells presumably play a major role in
maintenance of the shuttle.
Alzheimer’s Disease comprises the most abundant form of
dementia. Tau aggregates and Aβ- plaques are the early manifests
of the disease which results in neuronal death and successive
neurodegeneration [50]. In CNS different cell types are intrinsically
wired to maintain proper synaptic plasticity resulting in cognition
and memory function. In AD brain, activated microglia are the
major bearer of tau spreading and neuroinflammation [51]. The
inflammatory cytokines released by activated microglia are serious
threat for the neurons [52]. On the other hand, aberrantly activated
astrocytes in the diseased condition are uncooperative to take
the metabolic burden from neurons and this in turn can activate
the microglia to come close together and phagocytose the dying
neurons. Wnt signaling, being a central regulator of development
and neurogenesis [53] supposedly play a significant role in this
crosstalk which has not been investigated till now. GSK3β, one of the
intermediates of canonical Wnt signaling has been showed to regulate
Tau hyperphosphorylation and aggregation [54]. However, GSK3β can
also be regulated by Insulin signaling cascade through AKT [55]. So,
only pin-pointing GSK3β makes the role of Wnt signaling inconclusive
in the disease. Although, few reports mentioned about the variation
of specific Wnts in different cell types at mRNA level, the mechanistic
details are still missing [56]. Few reports suggest Wnt signaling as
beneficial but there are studies showing the detrimental role of this
signaling [57,58]. To address this question, Wnt signaling cascade
needs to be dissected in a cell-specific manner. With identification of
Wnt receptor ROR1 as a genetic risk factor [59], there is an urgency
to study the importance of this signaling in the disease. LRP1, a coreceptor
for many Wnt ligands also known to interact with Tau and
promotes Tau seeding in neurons [60]. Apoβ4, the strongest genetic risk factor of AD is known to regulate Wnt signaling pathway in neuroendocrine cells [61]. All these discrete studies are bringing Wnt
signaling into limelight for AD and demands more comprehensive
insight for the role of Wnt signaling and its intermediates in the
disease. Different modes of activation or inactivation of this signaling
may unlock some novel therapeutic interventions for the disease.
Right now there are more than 55 million Alzheimer’s Disease
patients worldwide and the number is expected to reach around 139
million by 2050 [62]. These increasing numbers expose the failure of
a successful therapeutic intervention for the disease. Wnt signaling
pathway has already been targeted in cancer and in some cases the
inhibitors are successful in restraining the disease [63-65]. In AD,
there is a lack of mechanistic insight about the role of Wnt signaling
in disease progression. Considering the significance of Wnt signaling
in neurogenesis, synaptic development and neuroinflammation, a
comprehensive study of this signaling pathway in AD may guide the
discovery of a successful treatment alternative.
Jati S, Sen M, Jati S, Sen M (2019) “Wnt Signaling Regulates Macrophage Mediated Immune Response to Pathogens.,” Macrophage Activation - Biology and Disease. IntechOpen.