Deletion of plasma Phospholipid Transfer Protein (PLTP) increases microglial phagocytosis and reduces cerebral amyloid-β deposition in the J20 mouse model of Alzheimer's disease.

Marine Mansuy,Laurent Givalois,Naig Le Guern,Valérie Deckert,Catherine Cohen-Solal,Véronique Perrier,Catherine Desrumaux,Geoffrey Canet,Nathalie Chevallier,Laurent Lagrost,Amélie Borie,Stella Baille,Michel Vignes

doi:10.18632/oncotarget.24802

Abstract

Plasma phospholipid transfer protein (PLTP) binds and transfers a number of amphipathic compounds, including phospholipids, cholesterol, diacylglycerides, tocopherols and lipopolysaccharides. PLTP functions are relevant for many pathophysiological alterations involved in neurodegenerative disorders (especially lipid metabolism, redox status, and immune reactions), and a significant increase in brain PLTP levels was observed in patients with Alzheimer's disease (AD) compared to controls. To date, it has not been reported whether PLTP can modulate the formation of amyloid plaques, i.e. one of the major histopathological hallmarks of AD.We thus assessed the role of PLTP in the AD context by breeding PLTP-deficient mice with an established model of AD, the J20 mice. A phenotypic characterization of the amyloid pathology was conducted in J20 mice expressing or not PLTP. We showed that PLTP deletion is associated with a significant reduction of cerebral Aβ deposits and astrogliosis, which can be explained at least in part by a rise of Aβ clearance through an increase in the microglial phagocytic activity and the expression of the Aβ-degrading enzyme neprilysin.PLTP arises as a negative determinant of plaque clearance and over the lifespan, elevated PLTP activity could lead to a higher Aβ load in the brain.

Highlights

Plasma phospholipid transfer protein (PLTP) belongs to the lipid transfer/lipopolysaccharide binding protein (LT/LBP) gene family as do cholesteryl ester transfer protein (CETP) and two proteins involved in innate immunity, lipopolysaccharide binding protein (LBP) and bactericidal permeability increasing protein (BPI) [1]
To address the impact of PLTP on pathways involved in Alzheimer’s disease (AD), we generated TgAPP mice lacking PLTP (TgAPP/PLTP–/–) and compared them with their TgAPP littermates at the age of 6 months
We provide evidence that cerebral Amyloid beta (Aβ) peptide deposition is markedly reduced when PLTP is deleted in a hAPP transgenic mouse model of AD, which can be explained by an increase in Aβ clearance mechanisms

Summary

Introduction

Plasma phospholipid transfer protein (PLTP) belongs to the lipid transfer/lipopolysaccharide binding protein (LT/LBP) gene family as do cholesteryl ester transfer protein (CETP) and two proteins involved in innate immunity, lipopolysaccharide binding protein (LBP) and bactericidal permeability increasing protein (BPI) [1]. Through its ability to transport the lipophilic antioxidant alpha-tocopherol, i.e. the main isomer of vitamin E, PLTP plays a major role in maintaining the redox equilibrium between the intravascular compartment and tissues, with reported pathophysiological implications in the fields of vascular homeostasis, fertility, and cognitive functions [5,6,7,8,9]. Last but not the least, PLTP has recently been reported to modulate inflammation and immune responses. These actions rely both on its ability to transport and detoxify lipopolysaccharides (the main component of the cellular wall of Gram-negative bacteria) [10,11,12] and on its direct action on immune cell functions [13, 14]. A positive relationship was established between PLTP activity and inflammatory markers in patients with cardiovascular disease or diabetes [15,16,17]

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