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