Astrocytes and Alzheimer’s


In the August issue of Nature Medicine,  researchers report on the role of astrocytes in memory loss in Alzheimer’s disease. Astrocytes, a type of glial cell in the brain, have been mostly thought of as a supporting cell in the nervous system, supporting neurons and acting as a glue for surrounding cells. More recently however, it has been shown that astrocytes play a much more important role, aiding in controlling the chemical environment around cells and even modulating chemical transmission between neurons. In fact, it has even been established that these cells can participate in chemical communication themselves, secreting their own neurotransmitters, soliciting responses in neighboring neurons.

Alzheimer’s disease (AD) is a neurodegenerative disease which results in the loss of memory and deterioration of other cognitive function. So far, suspects include plaques and tangles, abnormal protein aggregates that may interfere with normal cell function, though there is also evidence that these aggregates may not play a major role at all.

In this paper, researcher show that astrocytes, a non-neuronal cell capable of releasing neurotransmitter, play a role in AD through the release of the neurotransmitter GABA, the major inhibitory transmitter in the brain. Since the other major class of neurotransmitter is excitatory, GABA is able to act as a break on this other activity. Interestingly, it had previously been reported that patients with AD have elevated levels of GABA in cerebrospinal fluid, suggesting that GABA transmission may be elevated in the AD nervous system.

The authors use a mouse model of AD in which there is a mutation in the amyloid precursor protein and gamma-secretase, mutations associated with human AD. Importantly, these mice exhibit features of classic AD including plaques, memory impairment, and perhaps most importantly, reactive astrocytes (activated astrocytes that respond to surrounding damage). These reactive astrocytes tend to accumulate near the plaque deposits in the hippocampus of the brain, a neural structure important for learning and memory. In the hippocampus, the paper shows that astrocyte GABA was elevated by a factor of 5 as measured by staining for GABA markers.

Next, the researchers aimed to show that the reactive astrocytes actually release GABA. To do this, astrocytes were actually removed from slices of hippocampal tissue and individually probed with a technique that is able to stimulate the astrocytes while measuring responses to GABA. If GABA responses are observed after astrocyte stimulation, it suggests that the astrocytes are releasing this inhibitory transmitter. This is exactly what the researchers observed. The paper also shows that the increased levels of GABA are a result of increased activity of the enzyme Maob, an enzyme that has already been associated with AD. Interestingly, the GABA production caused by the Maob activity is the result of Beta-amyloid, the molecule that makes up the amyloid plaques associated with AD pathology. Perhaps most importantly, the authors show that inhibition of the Maob enzyme results in a rescue of both neuron excitability and synaptic plasticity/memory associated with this mouse model of Alzheimer’s disease.

This paper identifies a new role for astrocytes in disease pathophysiology. The authors show that astrocytes are able to release the inhibitory neurotransmitter GABA, altering the functionality of neighboring neurons and their ability to transmit electrical signals. Additionally, the authors were able to identify the pathway and enzyme responsible for the elevated levels of GABA and they showed that blockade of this enzyme can rescue some of the important deficits associated with this AD mouse model. This data is interesting as it suggests that astrocytes could be playing an important role in other neurodegenerative diseases, either through GABA release or maybe through the release of other neurotransmitters that astrocytes are known to be capable of releasing. The research presented here also identifies a pathway that can be targeted for drug treatment of Alzheimer’s disease as the authors show that inhibition of Maob in this study was able to rescue both learning/memory/synaptic plasticity in the AD mice.


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