Data availability statement
The data that support the findings of this study are available from the
corresponding author upon reasonable request. Some data may not be made
available because of privacy or ethical restrictions.
INTRODUCTION
Alzheimer’s disease (AD) is the most common dementia worldwide, with no
effective therapeutic strategies to date. The most characteristic
neuropathology of AD is the extracellular fibrillar
β-amyloid protein (Aβ) that
aggregates to form senile plaques (SPs), which is highly associated with
hyperphosphorylated tau protein, ectopic inflammatory stress and
neuronal loss, etc . The successive cleavage of
amyloid precursor protein (APP)
by β-site APP cleavage enzyme 1 (BACE1) and γ-secretase is the main
source of Aβ (Vassar et al., 1999). Furthermore, APP can also be cleaved
by α-secretase (ADAM10) to constitute a
nonamyloidogenic pathway
(Sisodia, 1992). According to these observations, strategies for
inhibiting Aβ production and promoting Aβ clearance from the brain were
developed to alleviate AD progression. However, the clinical trials of
BACE1 inhibitors failed, which may be ascribed to that the inhibitors
didn’t inhibit the expression or activity of BACE1, but elevated BACE1
expression by extending its half-life (Liu et al., 2019). Moreover, most
of the clinical trials of Aβ monoclonal antibody drugs were terminated
because of the poor efficacies and outstanding adverse events (Lu et
al., 2020). Therefore, developing novel strategies for the treatment of
AD is urged.
APP phosphorylation was elucidated to play a critical role in Aβ
generation. When phosphorylation of APP at Thr668, the APP is a tendency
to translocate to the endosomes where is an enrichment of BACE1, thus
promoting the Aβ production; in contrast, mutation of APP at Thr668 or
inhibition of p-APP(Thr668) expression decreased the Aβ production (Lee
et al., 2003). Furthermore, a recent study also revealed that the
phosphorylation of APP at Ser675 enhanced the Aβ production by promoting
the meprin β-mediated APP-processing at the plasma membrane (Menon et
al., 2019). These data suggest that inhibition of APP phosphorylation at
specific sites is a promising strategy to repress Aβ production.
Notably, the protein phosphatase 2A (PP2A) was known to
dephosphorylation of APP at Thr668 (Shentu et al., 2018), and enhanced
PP2A activity could effectively reduce the Aβ production by decreasing
the p-APP expression (Hu et al., 2022). However, the activity of PP2A
but not PP2A expression was significantly reduced in the brains of AD
patients (Sontag and Sontag, 2014), suggesting that upregulation of PP2A
activity is a hopeful strategy to relieve AD progression.
Lactoferrin (Lf), a secreted glycoprotein, is overexpressed in the
astrocytes and microglia as well as neurons in the brains of elderly
people and AD patients (Kawamata et al., 1993; Leveugle et al., 1994).
Recently, the decreased salivary Lf was identified as a specific
biomarker for AD (Gonzalez-Sanchez et al., 2020), while another study
also declaimed that the Lf in saliva and cerebrospinal fluid was
unchanged in the condition of AD (Gleerup et al., 2021). notably,
non-parametric machine learning analysis on transcriptomic data from a
large neuropathologically characterized patient cohort revealed that Lf
is a key predictor of Aβ pathology (Tsatsanis et al., 2021). Our
previous study revealed that exogenous Lf supplementation effectively
reduced Aβ production through upregulating ADAM10 in APP/PS1 mice (Guo
et al., 2017). A recent study also exerted beneficial actions of dietary
Lf in J20 mice via inhibiting
BACE1 expression and promoting Aβ clearance by astrocytes (Abdelhamid et
al., 2020). Given that the overexpression of Lf in astrocytes was
observed in the brains of AD patients (Kawamata et al., 1993), we
speculated that the astrocytic Lf may have beneficial effects on AD
progression. It is notable that Lf significantly activated p38
activation in MC3T3-E1 osteoblast cells (Liu et al., 2018), and p38 may
possess a potential role in regulating the PP2A activity (Grethe and
Porn-Ares, 2006), suggesting that the astrocytic Lf may regulate the Aβ
production via modulating PP2A-mediated APP dephosphorylation.
In this study, we investigated the roles of astrocytic Lf in AD
progression. Our study revealed that overexpression of astrocytic Lf
promoted the secretion of Lf from astrocytes, and Lf treatment
significantly elevated the PP2A activity by promoting the interaction of
p38 and PP2A to decrease APP phosphorylation; furthermore,
overexpression of astrocytic Lf reduced the Aβ burden via increasing the
PP2A-mediated APP dephosphorylation, resulting in the improvement of
cognitive capacity in APP/PS1 mice. Thus, promoting astrocytic Lf
expression may be a beneficial strategy for treating AD.
METHODS