Astrocytes are overtaxed neurons’ pit crew.
The brain cells collect damaged lipids secreted by hyperactive neurons, then recycle those toxic molecules into energy, researchers at the Howard Hughes Medical Institute’s Janelia Research Campus report May 23, 2019, in the journal Cell.
It’s a mechanism to protect neurons from the damaging side effects of overactivity.
And it’s another important role for astrocytes, which support neurons in various ways.
When a neuron fires fast and furious, lipid molecules in the cell get damaged and can become toxic.
While most kinds of cells sequester excess fatty acids away or feed them to mitochondria to prevent buildup, neurons don’t seem to rely on those tricks.
Instead, “neurons unload some of the burden to astrocytes,” says study coauthor and Janelia Group Leader Zhe Liu, who worked closely with Maria Ioannou and Jennifer Lippincott-Schwartz, a senior group leader at Janelia.
“For a long time, people have suspected there was some mechanism like this.
The new work shows how this process actually happens.”
The finding arose from a curious observation: Overactive neurons release damaged fatty acids bundled up in lipid particles.
“People didn’t think that neurons could secrete those lipid particles,” Liu says.
But stimulating mouse neurons in a dish led to the buildup of fatty acids and, eventually, lipid particle release, the team showed.
Then, nearby astrocytes engulfed the particles and amped up the activity of genes involved in energy production and detoxification.
Astrocytes feed neurons’ off-loaded damaged lipids to their own mitochondria, converting waste into energy, Liu concluded.
Tests in mice showed a similar response.
After a lesion to the brain that mimics a stroke – a huge stress to neurons – neurons increased production of proteins involved in transporting fatty acids out of the cell, and fatty acids built up in astrocytes.
This pathway for clearing toxic molecules from neurons might be damaged in Alzheimer’s patients, Liu proposes, though that hasn’t been thoroughly investigated.
A next step, led by Maria Ioannou in her new lab at the University of Alberta, is to examine what’s different about this mechanism in cell culture and rodent models of Alzheimer’s disease.
Astrocytes play a critical role in the viability and function of the central nervous system (CNS). As reviewed in other articles in this monograph series, astrocytes play integral roles in the formation, maintenance, and elimination of synapses in development and disease (reviewed in Chung and Barres 2012).
The release of vasoactive substances, such as prostanoids from astrocytes, can couple cerebral blood flow to neuronal energy demand, and astrocytes supply neurons with vital metabolites, such as lactate in response to neuronal activity (reviewed in Allaman et al. 2011).
Additional homeostatic functions of astrocytes include water, ion, and glutamate buffering, as well as tissue repair after insult or injury (reviewed in Stevens 2008; Belanger and Magistretti 2009; Perea et al. 2009; Sofroniew and Vinters 2010; Allaman et al. 2011; Sidoryk-Wegrzynowicz et al. 2011; Chung and Barres 2012).
In light of the central role played by astrocytes in the function of the CNS, it is not surprising that they have also been implicated in the onset and progression of neurodegenerative diseases.
The question of whether the involvement of astrocytes in these diseases is a consequence of the loss of their normally supportive roles (loss-of-function), or to a toxic gain-of-function, or both, is currently under active investigation.
Here, we review the role of astrocytes in neurodegenerative diseases, focusing on their dysfunction in Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS).
Role of Astrocytes in Neurological Disease—Loss of Normal Function or Gain of Toxic Function?
Astrocytes are required for neuronal survival (Wagner et al. 2006), and the loss of normal astrocyte function can be a primary contributor to neurodegeneration (Brenner et al. 2001; Li et al. 2005; Quinlan et al. 2007).
For example, disorders, such as Alexander disease and hepatic encephalopathy (HE), are a consequence of astrocyte dysfunction. Alexander disease is a leukodystrophy, caused by autosomally dominant mutations in the gene fibrillary acidic protein (GFAP).
The disease is characterized by intra-astrocytic protein aggregates, consisting of mutant GFAP, heat shock protein 27, and αβ-crystallin (Brenner et al. 2001; Li et al. 2005; Quinlan et al. 2007).
These aggregates, called Rosenthal fibers, are thought to compromise normal astrocytic functions, leading to the abnormal myelination and neurodegeneration characteristic of this disease.
Hepatic encephalopathy, a neuropsychiatric syndrome that results from liver disease, is another example of how dysfunctional astrocytes can be a primary cause of neurological disease (reviewed in Felipo and Butterworth 2002; Haussinger and Schliess 2008; Butterworth 2010).
Acute or chronic liver disease leads to the accumulation of high concentrations of ammonia in the brain; this ammonia is primarily detoxified by astrocytic glutamine synthase.
This detoxification results in the intracellular accumulation of osmotically active glutamine; the accumulation of glutamine leads to astrocytic swelling and changes in expression of key astrocyte proteins, such as the glutamate transporter GLT-1, the aquaporin Aqp4, the glucose transporter GLUT1, and GFAP.
The cytotoxic astrocytic swelling and alterations of key astrocytic proteins, in turn, can alter the normal astrocytic functions required to maintain CNS homeostasis.
Reactive Gliosis—Complex Interplay between Neurotoxic and Neuroprotective Processes
Reactive astrogliosis is the response of astrocytes to insult or injury in the CNS (reviewed in Sofroniew 2009; Sofroniew and Vinters 2010). Reactive gliosis is a graded response that encompasses a spectrum of changes that range from hypertrophy to proliferation and migration (discussed in Sofroniew 2009).
The nature and extent of the astrocytic response is determined by the context in which it occurs and by the duration and nature of the instigating stimulus.
For example, lipopolysaccharide (LPS), stroke, and neurodegenerative disease can induce very different kinds of reactive gliosis (Zamanian et al. 2012; Phatnani et al. 2013).
Reactive astrocytes can release a wide variety of extracellular molecules, including inflammatory modulators, chemokines and cytokines, and various neurotrophic factors.
These factors can be either neuroprotective (e.g., cytokines, such as interleukin-6 [IL-6] and transforming growth factor-β [TGF-β]) or neurotoxic (such as IL-1β and tumor necrosis factor-α [TNF-α]) (reviewed in Sofroniew 2009).
The interplay between the neuroprotective and neurotoxic effects of reactive gliosis is exemplified by the process of glial scar formation.
The glial scar serves to isolate the damaged area and prevents the spread of damage by restricting the infiltration of inflammatory cells. However, molecules secreted by reactive scar-forming astrocytes can also be refractory to neurite growth (reviewed in Sofroniew 2009).
Dissecting various aspects of astrocyte responses to tissue injury has shed light on which signaling pathways are beneficial and which can be deleterious. For example, inflammatory signaling through STAT3 can be neuroprotective. Astrocyte-specific deletion of STAT3 impairs reactive gliosis, leads to increased inflammation and tissue damage, and compromises motor recovery after spinal cord injury (SCI) (Okada et al. 2006; Herrmann et al. 2008).
On the other hand, inflammatory signaling in astrocytes can also be neurotoxic. Inhibition of astroglial NF-κB resulted in limiting tissue injury and impaired functional recovery after contusive SCI (Brambilla et al. 2005).
This also increased neuronal sparing and sprouting of spinal tract axons (Brambilla et al. 2009a), increased neuronal survival in the retinal glial cell (RGC) layer after ischemia-reperfusion injury (Dvoriantchikova et al. 2009), and reduced disease incidence and severity and promoted significant functional recovery in murine experimental autoimmune encephalomyelitis (EAE) (Brambilla et al. 2009b). Activation of NF-κB in astrocytes is also thought to contribute to pathogenesis in HD (Hsiao et al. 2013).
However, blocking NF-κB activation in astrocytes in an ALS mouse model in vivo did not result in a change of disease progression (Crosio et al. 2011).
The investigators of this paper concluded that “motor neuron death in ALS cannot be prevented by inhibition of a single inflammatory pathway because alternative pathways are activated in the presence of a persistent toxic stimulus.”
More information: Maria S. Ioannou et al, Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity, Cell(2019). DOI: 10.1016/j.cell.2019.04.001
Journal information: Cell
Provided by Howard Hughes Medical Institute
