1. Intercellular (Mis)communication in Neurodegenerative Disease
Gwenn A. Garden, Albert R. La Spada 
Neuron 
Volume 73, Issue 5, Pages (March 2012)
DOI: /j.neuron
Copyright © 2012 Elsevier Inc. Terms and Conditions

2. Figure 1
A Variety of Non-Cell-Autonomous Factors Influence Neuronal Survival
Neurons receive synaptic input (1), delivering both neurotransmitters and neurotrophic factors (2) that sustain neuronal survival. Neurodegenerative diseases can alter synaptic input by inhibiting anterograde axonal transport (3) and/or axon degeneration (4), resulting in decreased release of transmitters and neurotrophic peptides. (5) Failed retrograde transport as well as molecular dysfunction in target neurons or in non-neural target organs (e.g., muscle and blood vessels) can also damage presynaptic neurons, mimicking events that occur during development, when pathways of target-dependent neuronal survival are active.
Neuron  , DOI: ( /j.neuron )
Copyright © 2012 Elsevier Inc. Terms and Conditions

3. Figure 2 Astrocyte Dysfunction in Neurodegenerative Disease
Astrocytes perform a variety of functions reflecting their communication and close interactions with neurons. Here we see a representative astrocyte (blue) engaging in various activities, which when disrupted or altered, can lead to dysfunction and degeneration of neurons (green):
(A) Astrocytes (blue) release neurotrophic factors (yellow smiley faces), and loss of neurotrophic factor release has been implicated in a number of neurological disorders. Alternatively, astrocytes can release toxic factors (red frown faces), which are believed to be a feature of motor neuron disease and possibly other disorders, as delineated in the section on Astrocyte-Derived Toxicity.
(B) Neurons (green) release neurotransmitters to propagate signals between each other, and these neurotransmitters must be removed from the synaptic cleft in order to prevent persistent activation, a pathological process known as “excitotoxicity.” Astrocytes (blue) have transporters on their cell membranes to mediate neurotransmitter uptake, and impairment in neurotransmitter uptake by astrocytes can contribute to neuron dysfunction and degeneration.
(C) Astrocytes (blue) shuttle metabolites (e.g., lactate) between blood vessels (red) and neurons (green), as shown here. Disturbances in this metabolic coupling can result in neuron dysfunction.
(D) Astrocytes form the blood brain barrier in cooperation with cells lining blood vessels. The breakdown of the blood-brain barrier at the level of the astrocyte may also occur in certain neurodegenerative diseases.
Neuron  , DOI: ( /j.neuron )
Copyright © 2012 Elsevier Inc. Terms and Conditions

4. Figure 3 Microglia Play Divergent Roles during Neurodegeneration
In the healthy CNS, microglia survey their immediate environment, and in this “resting state,” do not express inflammatory mediators. However, after exposure to a number of chemical signals from damaged neurons, microglia respond rapidly and physically migrate to the site of injury. Responding microglia may then adopt a pattern of behavior similar to proinflammatory macrophages (shown in red), as they release molecules intended to protect against pathogens, including neurotoxic cytokines, reactive oxygen species (ROS), and small molecules, such as quinolinic acid, that promote excitotoxicity. The release of cytokines and chemokines can lead to the recruitment of additional inflammatory cells from adjacent blood vessels, and may also engage astrocytes in the proinflammatory response. Alternatively, activated microglia may exhibit behaviors associated with anti-inflammatory macrophages (shown in green), secreting molecules that promote tissue repair, and internalizing cellular debris including aggregated, misfolded proteins such as β-amyloid, through phagocytosis. Whether two distinct populations of microglia exist that are committed to either of these response patterns, or all microglia can be induced to exhibit either response behavior when exposed to the correct combination of signals, remains to be determined.
Neuron  , DOI: ( /j.neuron )
Copyright © 2012 Elsevier Inc. Terms and Conditions

5. Figure 4
Proposed Mechanisms to Account for Cell-to-Cell Transmission of Misfolded Proteins
(A) Exocytosis/endocytosis. Misfolded proteins can be packaged into exocytotic vesicles (top left; arrows), which fuse with the cell membrane and release their contents into the extracellular space. Misfolded proteins may be delivered to preautophagic vesicles that mature into double-membrane bound autophagosomes (top right; arrows). One possible fate of certain autophagosomes is to fuse with the cell membrane and release their contents into the extracellular space. Once in the extracellular space, misfolded proteins can be taken up by cells via lipid raft-mediated endocytosis (bottom left; zigzags represent lipid rafts), or more likely by receptor-mediated endocytosis (bottom right; half rectangle with oval indentation represents receptor).
(B) Propagation without membrane-bound transport. Misfolded proteins may move from one cell to another via intercellular bridges, known as “tunneling nanotubes” (left; arrows). Another route for cell-to-cell transfer of misfolded proteins is within exosomes, small membrane-bound vesicles (green circles) that can form within multivesicular bodies (orange circle), which are released and endocytosed by a neighboring cell (right; arrows). Such exosomes can bud off of their original cell and travel large distances before fusing with the membrane of another cell. How misfolded protein conformers, sequestered in endosomes, gain access to the cytosolic compartment remains unclear.
Neuron  , DOI: ( /j.neuron )
Copyright © 2012 Elsevier Inc. Terms and Conditions