Intranasal Lactoferrin Enhances α-Secretase-Dependent Amyloid Precursor Protein Processing via the ERK1/2-CREB and HIF-1α Pathways in an Alzheimer’s Disease Mouse Model

Abstract

Growing evidence suggests that lactoferrin (Lf), an iron-binding glycoprotein, is a pleiotropic functional nutrient. In addition, Lf was recently implicated as a neuroprotective agent. These properties make Lf a valuable therapeutic candidate for the treatment of Alzheimer's disease (AD). However, the mechanisms regulating the physiological roles of Lf in the pathologic condition of AD remain unknown. In the present study, an APPswe/PS1DE9 transgenic mouse model of AD was used. We explored whether intranasal human Lf (hLf) administration could reduce β-amyloid (Aβ) deposition and ameliorate cognitive decline in this AD model. We found that hLf promoted the non-amyloidogenic metabolism of amyloid precursor protein (APP) processing through activation of α-secretase a-disintegrin and metalloprotease10 (ADAM10), resulting in enhanced cleavage of the α-COOH-terminal fragment of APP and the corresponding elevation of the NH2-terminal APP product, soluble APP-α (sAPPα), which consequently reduced Aβ generation and improved spatial cognitive learning ability in AD mice. To gain insight into the molecular mechanism by which Lf modulates APP processing, we evaluated the involvement of the critical molecules for APP cleavage and the signaling pathways in N2a cells stably transfected with Swedish mutant human APP (APPsw N2a cells). The results show that the ERK1/2-CREB and HIF-1α signaling pathways were activated by hLf treatment, which is responsible for the expression of induced ADAM10. Additional tests were performed before suggesting the potential use of hLf as an antioxidant and anti-inflammatory. These findings provide new insights into the sources and mechanisms by which hLf inhibits the cognitive decline that occurs in AD via activation of ADAM10 expression in an ERK1/2-CREB and HIF-1α-dependent manner.

Iron and Alzheimer’s Disease: From Pathogenesis to Therapeutic Implications

“…In fact, it has been reported in the literature that the function of human LF is similar to that of the iron chelator DFO, and it can also induce the neuroprotective effect of hypoxia-inducible factor (HIF-1α) expression under hypoxic conditions ( Kawamata et al, 1993 ). Specifically, our results suggested that LF can enhance the α-secretase-dependent APP process through the ERK1/2-CREB and HIF-1α pathways in vitro and in vivo ( Guo et al, 2017 ), once again proving that LF plays an active role in the treatment of AD. Consistent with previous observations, Aizawa et al (2017) recently reported that the binding of LF to low-density lipoprotein receptor-associated protein-1 (LRP1) leads to the activation of the AMP-activated protein kinase signaling pathway, which in turn, promotes cell autophagy.…”

“…Studies have also shown that an imbalance of metal homeostasis can directly cause neuronal dysfunction ( Myhre et al, 2013 ) and lead to neuronal cell death ( Wright and Baccarelli, 2007 ). Moreover, the successful application of metal (zinc, copper, iron) chelators in several animal models of AD and patients with early AD provided strong evidence that AD is a transition metal-overloading disease ( Guo et al, 2013b , 2015 , 2017 ; Dusek et al, 2016 ; Giampietro et al, 2018 ; Kawahara et al, 2018 ; Zhang et al, 2018 ). Based on the research described above, the metal ion hypothesis was proposed to emphasize the role of metal ions in the pathogenesis of AD, which further complemented the pathogenesis of AD.…”

“…Therefore, the use of exogenous LF as a therapeutic agent has been investigated to identify its roles in AD. Our group was the first to investigate whether exogenous LF administration could stimulate the non-amyloidogenic processing of APP and α-secretase catalytic activity and expression, which consequently reduce Aβ deposition and ameliorate cognitive decline in AD model mice ( Guo et al, 2017 ). We also addressed the molecular mechanisms by which LF modulates APP processing.…”

Decreased salivary lactoferrin levels are specific to Alzheimer’s disease

“…Lf is known to be transferred from the sublingual mucosa to the brain [42]. In this context, favourable Lf effects on brain are expected, and they could be related to its antimicrobial capacity but also they may stimulate the non-amyloidogenic processing of APP and the α-secretase catalytic activity and expression in a mouse model of AD [43].…”

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

“…[15][16][17] These findings suggest that Lf is a suitable ligand to mediate enhanced nose-to-brain delivery of formulations after intranasal administration. [18][19][20] Huperzine A (HupA) is a reversible inhibitor of acetylcholinesterase (AChE) in a club moss (Huperzia serrata), which enhances memory in behavioral animal models. [21][22][23] Studies have shown that HupA exerts multiple neuroprotective effects in addition to inhibition of AChE.…”