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 (0.3 mg/kg/day) or vehicle for 8 weeks 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.

Transporters as Drug Targets in Neurological Diseases

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Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial

“…However, the absorption and distribution of the methylthioninium moiety is complex, and plasma concentrations do not reflect brain concentration. 14 Avenues being explored include further blood analyses, the potential effect of cholinergic pathology on cognition and brain atrophy 27 in tau transgenic mouse models, the interaction between cholinesterase and amyloid pathology, 28 and whether induction of transporters by chronic administration of symptomatic treatments for Alzheimer’s disease 29,30 might lower the concentration of methylthioninium at the site of action.…”

Identification of embelin, a 3‐undecyl‐1,4‐benzoquinone from Embelia ribes as a multitargeted anti‐Alzheimer agent

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