title: Role of P-glycoprotein in mediating rivastigmine effect on amyloid-β brain load and related pathology in Alzheimer's disease mouse model.
abstract: Recently, we showed that rivastigmine decreased amyloid-β (Aβ) brain load in aged rats by enhancing its clearance across the blood-brain barrier (BBB) via upregulation of P-glycoprotein (P-gp) and low-density lipoprotein receptor-related protein 1 (LRP1). Here, we extend our previous work to clarify P-gp role in mediating rivastigmine effect on Aβ brain levels and neuroprotection in a mouse model of Alzheimer's disease (AD) that expresses different levels of P-gp. APPSWE mice were bred with mdr1a/b knockout mice to produce littermates that were divided into three groups; APP(+)/mdr1(+/+), APP(+)/mdr1(+/-) and APP(+)/mdr1(-/-). Animals received rivastigmine treatment (0.3mg/kg/day) or vehicle for 8weeks using Alzet osmotic mini-pumps. ELISA analysis of brain homogenates for Aβ showed rivastigmine treatment to significantly decrease Aβ brain load in APP(+)/mdr1(+/+) by 25% and in APP(+)/mdr1(+/-) mice by 21% compared to their vehicle treated littermates, but not in APP(+)/mdr1(-/-) mice. In addition, rivastigmine reduced GFAP immunostaining of astrocytes by 50% and IL-1β brain level by 43% in APP(+)/mdr1(+/+) mice, however its effect was less pronounced in P-gp knockout mice. Moreover, rivastigmine demonstrated a P-gp expression dependent neuroprotective effect that was highest in APP(+)/mdr1(+/+)>APP(+)/mdr1(+/-)>APP(+)/mdr1(-/-) as determined by expression of synaptic markers PSD-95 and SNAP-25 using Western blot analysis. Collectively, our results suggest that P-gp plays important role in mediating rivastigmine non-cholinergic beneficial effects, including Aβ brain load reduction, neuroprotective and anti-inflammatory effects in the AD mouse models.
authors.affiliation: Department of Basic Pharmaceutical Science, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Dr., Monroe, LA 71201, United States.
authors.forename: Loqman A
authors.initials: LA
authors.lastname: Mohamed
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, United States.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Keller
authors.affiliation: Department of Basic Pharmaceutical Science, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Dr., Monroe, LA 71201, United States. Electronic address: kaddoumi@ulm.edu.
authors.forename: Amal
authors.initials: A
authors.lastname: Kaddoumi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D000068836:Rivastigmine / Q000493:pharmacokinetics / Q000494:pharmacology*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism
chemical_list: C545487:APP protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016564:Amyloid beta-Protein Precursor; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D000068836:Rivastigmine
keywords: Alzheimer's disease; Amyloid-beta; Astrogliosis; Neuroprotection; P-glycoprotein; Rivastigmine