Abstract
Recent findings indicate that microglia in Alzheimer’s disease (AD) is senescent whereas peripheral blood mononuclear cells (PBMCs) could infiltrate the brain to phagocyte amyloid deposits. However, the molecular mechanisms involved in the amyloid peptide clearance remain unknown. Autophagy is a physiological degradation of proteins and organelles and can be controlled by pro-inflammatory cytokines. The purpose of this study was to evaluate the impact of inflammation on autophagy in PBMCs from AD patients at baseline, 12 and 24 months of follow-up. Furthermore, PBMCs from healthy patients were also included and treated with 20 μM amyloid peptide 1–42 to mimic AD environment. For each patient, PBMCs were stimulated with the mitogenic factor, phytohaemagglutin (PHA), and treated with either 1 μM C16 as an anti-inflammatory drug or its vehicle. Autophagic markers (Beclin-1, p62/sequestosome 1 and microtubule-associated protein-light chain 3: LC3) were quantified by western blot and cytokines (Interleukin (IL)-1β, Tumor necrosis Factor (TNF)-α and IL-6) by Luminex X-MAP® technology. Beclin-1 and TNF-α levels were inversely correlated in AD PBMCs at 12 months post-inclusion. In addition, Beclin-1 and p62 increased in the low inflammatory environment induced by C16. Only LC3-I levels were inversely correlated with cognitive decline at baseline. For the first time, this study describes longitudinal changes in autophagic markers in PBMCs of AD patients under an inflammatory environment. Inflammation would induce autophagy in the PBMCs of AD patients while an anti-inflammatory environment could inhibit their autophagic response. However, this positive response could be altered in a highly aggressive environment.
Highlights
Microglia represents the immunological effector cells in the central nervous system (CNS) that continuously survey the cellular environment in the brain parenchyma [1, 2]
As it is difficult to recruit healthy patients for a longitudinal study, we studied the functionality of autophagy and the inflammatory response of peripheral blood mononuclear cells (PBMCs) from healthy patients cultured in different conditions as explained below
This study describes the first modifications of the expression of autophagic markers in PHAstimulated PBMCs of Alzheimer’s disease (AD) patients with a negative correlation with the Beclin-1 and TNF-α levels at 12 months follow-up
Summary
Microglia represents the immunological effector cells in the central nervous system (CNS) that continuously survey the cellular environment in the brain parenchyma [1, 2]. Microglia mainly operates as scavenger cells, producing a wide spectrum of molecules that are essential for the clearance of invading pathogens and toxic factors [such as the aggregated misfolded proteins found in Alzheimer’s disease (AD)] and for tissue homeostasis, repair and renewal [1, 2]. This neuroprotective role in AD might depend on intrinsic or extrinsic age-related changes [microenvironment, dysfunction of blood brain barrier (BBB)]. Neither the amyloid plaque formation and maintenance nor the amyloid-associated neuritic dystrophy depends on the presence of microglia as demonstrated in two different transgenic models of AD crossed with mice expressing an inducible suicide gene, leading to the depletion of resident microglia [7]
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