title: 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.
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Chuang
authors.initials: C
authors.lastname: Guo
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Yang
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chai
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Han
authors.initials: H
authors.lastname: Xue
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Yan-Hui
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Li
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007781:Lactoferrin / Q000008:administration & dosage*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018697:Nootropic Agents / Q000008:administration & dosage*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation
chemical_list: D016564:Amyloid beta-Protein Precursor; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C490098:LTF protein, human; D018696:Neuroprotective Agents; D018697:Nootropic Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053829:Amyloid Precursor Protein Secretases; D007781:Lactoferrin