The Role of Glial Cells in Alzheimer’s Disease

According to the World Health Organisation (WHO), 35.6 million people worldwide suffer of dementia with 7.7 million new cases each year, and 60-70% of these patients have Alzheimer’s disease. After cancer, Alzheimer’s is the most prominent disorder of the 21st century and the number of people suffering from Alzheimer’s is expected to double every 20 years until 2040.

Alzheimer’s disease is characterised by progressive cognitive decline usually beginning with impairment to the ability to form short-term memories followed, inevitably, by decline in intellectual function, leading to complete dependence for basic functions, and eventually premature death. It is also a disorder that places a considerable strain on caregivers, families and society at the physical, psychological, social and economic levels. For these reasons and for scientific curiosity, Alzheimer’s continues to be the subject of many investigative studies.

The pathological implication of Alzheimer’s is multifaceted and includes diffuse and neuritic extracellular amyloid plaques and intracellular neuro fibrillary tangles accompanied by reactive microgliosis, dystrophic neuritis and loss of neurons and synapses. The underlying causes remain unknown but advancing age and genetic/nongenetic factors are thought to play important roles in the susceptibility to developing Alzheimer’s disease.

Here we take a look at the work of Seonmi Jo of the Korea Advanced Institute of Science and Technology on the role reactive astrocytes play in Alzheimer’s.

Astrocytes are glial cells found in the brain and spinal cord that outnumber neurons 5:1, and one of their many functions involve the formation of glial scars. The glial scar is the mechanism by which the nervous system begins to repair after suffering injury. Although not completely understood, it is thought that when the central nervous system suffers an injury, astrocytes become reactive leading to the expression of gliotransmitter proteins that cascade into the repair mechanisms needed. In Alzheimer’s, astrocytes have been found to be reactive; however, very few studies have looked at the consequence of reactive astrocytes to memory impairment.

A study by Yoshiike et al in 2008 suggested that increased activity of GABA (a major inhibitory transmitter in adult mammalian brains) leads to memory impairment in patients with Alzheimer’s. Having that in mind, Jo and colleagues hypothesised that abnormal increase in tonic GABA release from reactive astrocytes in the hippocampus may be directly responsible for memory impairment these patients. Using a mouse model they confirmed that the dentate gyrus (critical area for the formation and recall of memories) was one of the main areas in the brain that showed an accumulation of amyloid plaques and reactive astrocytes and that no neuronal death had occurred at 11 or 12 months of age. Further analysis of samples revealed that AD mice showed significantly elevated levels of GABA in the dentate gyrus when compared to wild-type (WT) mice and that the frequency and amplitude of spontaneous inhibitory post-synaptic currents were not altered in AD mice compared to WT mice. However, the tonic release in AD mice was significantly larger. These findings suggest that the abnormal elevation of GABA levels in the dentate gyrus of AD mice might be responsible for the increase in tonic GABA current.

Having established that GABA levels were elevated in AD mice, the source of GABA neutrotransmitters needed to be confirmed. Through immunostaining procedures with anti-GABA antibodies, analysis of the molecular level of the dentate gyrus and direct measurements of GABA release from single astrocytes in the hippocampus, the authors confirmed that reactive astrocytes in the dentate gyrus were expressing GABA abnormally in AD mice. Also consistent with previous study was the increased expression and activity levels of MaoB (a key enzyme in the putrescine degradation pathway) in AD mice. Using selective irreversible inhibitors of MaoB the authors were able to prove that MaoB has a role in the production of GABA in reactive astrocytes, since the immunoreactivity of GABA was significantly reduced post administration of the MaoB inhibitor. Observations to the spike probability in dentate gyrus neurons after administration of selective inhibitors of MaoB showed that there is an inverse relation between GABA levels and spike probability. Taken together, these results suggest that high levels of GABA is related to inhibited synaptic transmission and that inhibition of MaoB returns synaptic transmission to normal in AD mice.

In order to test whether inhibiting MaoB restores synaptic plasticity and memory, the mice undertook the Morris water maze test, which is a widely known test for hippocampus-dependent learning and memory. As expected, the AD mice performed worse when compared to WT mice; post-administration of MaoB inhibitors the test revealed a partial increase in memory and learning. This directly implicates MaoB, and by extension GABA, to memory and learning impairment in AD mice.

In summary, Jo et al show that reactive astrocytes have increased expression/release of GABA neutrotransmitter, which in turn inhibits synaptic release and causes diminished spike probability and impairment of synaptic plasticity and memory function. Importantly, the authors showed that inhibition of MaoB led to partial restoration of memory function, which may lead to the development of new treatment strategies involving glial cells. This is the first study what shows the involvement of glial cells in memory impairment in AD, and is a gateway into further investigation into the role other gliotransmitters play in AD and other brain disorders.

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