Astrocytes are one of a number of different classes of supporting cells of the brain, and researchers here investigate how they might be involved in the progression of Alzheimer's disease - though with the caution they they are looking at early-onset Alzheimer's linked to specific mutations. These variants of the condition may be accelerated by processes that are not relevant in the more common form. Either way, Alzheimer's disease is an enormously complex condition; all cell types in the brain change their behavior or are impacted in some way by inflammation, rising levels of protein aggregates such as amyloid-β, or other aspects of aging. Separating cause and effect of the disease state from everything else is a challenging undertaking, not least because the animal species used in the laboratory do not naturally suffer any sort of condition resembling Alzheimer's. So there is always the question of whether or not the very artificial animal models of the disease are close enough to the human condition to steer research in the right direction. This is the case for the biology of astrocytes in particular, and so the researchers here adopt a more modern approach of generating cells for study from human patients.
Alzheimer's disease (AD) is the most common dementia type, with no treatment to slow down the progression of the disease currently available. The mechanisms of AD are poorly understood, and drug therapy has focused on restoring the normal function of neurons and microglia, i.e. cells mediating brain inflammation. The new study shows that astrocytes, also known as the housekeeping cells of the brain, promote the decline of neuron function in AD. The findings suggest that at least some familial forms of AD are strongly associated with irregular astrocyte function, which promotes brain inflammation and weakens neurons' energy production and signalling.
Astrocytes are important brain cells, as they support neurons in many different ways. Astrocytes are responsible, for example, for the energy production of the brain, ion and pH balance, and they regulate synapse formation, the connections between neurons. Recent evidence suggests that human astrocytes are very different from their rodent counterparts and thus, it would be essential to use human cells to study human diseases. However, the availability of human astrocytes for research has been very limited. The study used the induced pluripotent stem cell technology, which enables the generation of pluripotent stem cells from human skin fibroblasts. These induced stem cells can then be further differentiated to brain cells, e.g. neurons and astrocytes, with the same genetic background as the donor had. The study compared astrocytes from familial AD patients carrying a mutation in the presenilin 1 gene to astrocytes from healthy donors, and the effects of these cells on healthy neurons were also analysed.
The researchers found out that astrocytes in patients with Alzheimer's disease produced significantly more beta-amyloid than astrocytes in persons without AD. Beta-amyloid is a toxic protein that is known to accumulate in the brains of AD patients. In addition, AD astrocytes secreted more cytokines, which are thought to mediate inflammation. AD astrocytes also showed alterations in their energy metabolism which likely led to increased production of reactive oxygen species and reduced production of lactate, an important energy substrate for neurons. Finally, when astrocytes were co-cultured with healthy neurons, AD astrocytes caused significant changes on the signaling activity of neurons when compared to healthy astrocytes.