Autophagy, inflammation and neurodegenerative disease

Abstract

Autophagy is emerging as a central regulator of cellular health and disease and, in the central nervous system (CNS), this homeostatic process appears to influence synaptic growth and plasticity. Herein, we review the evidence that dysregulation of autophagy may contribute to several neurodegenerative diseases of the CNS. Up-regulation of autophagy may prevent, delay or ameliorate at least some of these disorders, and - based on recent findings from our laboratory - we speculate that this goal may be achieved using a safe, simple and inexpensive approach.

© 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Figures

Figure 1. Summary of proposed mechanism of HIV-mediated neurodegeneration

HIV-infected cells, in particular infected monocytes/macrophages and CD4+ T cells, enter the CNS by crossing the blood-brain barrier in a process termed diapedesis (A). The introduction of infection into the CNS leads to the activation of microglia, either directly (by infection, B) or indirectly (C). These activated microglia produce a variety of cytokines and chemokines (D) with pleiotropic effects, including the activation of astrocytes (E). This leads to an increase in astrocyte abundance (astrocytosis) but, despite the increase in cell numbers, there is a decrease in a key astrocytic function: the resorption of glutamate (F). The increase in extracellular glutamate, acting via the N-methyl-D-aspartic acid (NMDA) receptor, can produce an excessive influx of Ca2+ into neurons (G) with consequent free-radical formation (H), leading to Ca2+ excitotoxicity (Berliocchi et al., 2007). In addition, viral proteins shed from infected microglia (I) may have neurotoxic effects that can be indirect (acting via astrocytes, J) or direct (K). ROS formation also activates intracellular calpain and, as described in the text, this causes a marked disruption of neuronal autophagy, with a reduction in the abundance of autophagosomes in neurites (L). This, in turn, leads to an increase in intra-neuronal protein aggregates (M) and neurodegeneration (N).

Figure 2. Proposed interactions between inflammation, Ca2+ excitotoxicity, and autophagy in a non-infectious neurodegenerative disease

During MS, lymphocytes infiltrate into the brain and recognize their antigen, usually myelin-derived antigen presented by an APC (A). These activated T cells then release pro-inflammatory cytokines that act on oligodendrocytes (B), leading to the demyelination that is a hallmark of the disease. This diagram focuses mainly on other events that may be involved in MS neurodegeneration. Atg5 is an important component of the autophagy pathway, and its cleavage can switch a cell’s fate from autophagy (and survival) to apoptosis (and death) (Yousefi et al., 2006). In our recent paper (Alirezaei et al., 2009) we showed that peripheral blood CD4+ T cells of some MS patients contained an elevated level of Atg5, leading us to speculate that these potentially-pathogenic cells may have prolonged lifespans (C). B cells and plasma cells, too, have been implicated in MS (D). The pro-inflammatory mediators that are released by activated lymphocytes and / or microglia (E) can activate astrocytes (F), reducing their capacity of resorb glutamate (G). The resulting increase in extracellular glutamate triggers AMPA receptors (H) which leads to an influx of Ca2+ into the neurons (Williams et al., 2008). This initiates a cascade of events including damage to mitochondria (I), an increase in ROS (J), activation of caspases and calpain, and a decrease in number of neurite autophagosomes (K). The ultimate outcome is neurodegeneration (L).

Figure 3. Food restriction induces autophagy in cortical neurons and Purkinje cells

Panel A. Autophagosomes (bright green punctae) in cortical neurons (left) and Purkinje cells (right) of GFP-LC3 mice after 48 hrs of food restriction. Panel B. Images of cerebellar sections stained with an antibody specific for phospho-S6RP (red), a protein whose abundance varies directly with mTOR activity, and inversely with autophagy. GFP-LC3, which is expressed at high levels in Purkinje cells, is shown in green and nuclei are stained with Hoechst dye (blue). Purkinje neurons in a normal fed animal (left) have high mTOR activity (indicating low autophagy) while cells in the 48 hrs food-restricted animal (right) have low mTOR activity (and, thus, a highly active autophagy pathway). Images were generated using Imaris software, blended mode (Bitplane, Inc). Panel C. A transmission electron microscope image of a single Purkinje cell from a 48 hour food-restricted mouse is shown. Autophagosomes are enclosed in colored boxes, and a higher-magnification image of each is provided.