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The role of non-neuronal cells in neurodegeneration

The brain contains not only neurons, but several types of non-neuronal cells (glia), and a correct interaction with the glia is essential for the health of the neurons. One of the 3 main types of glia are called astrocytes, and the DNF, with its collaborator the Centre for Psychiatric Neuroscience (CPN) at Cery, near Lausanne, constitutes one of the world's leading centres for research on astrocyte-neuron interaction. Much of this research concerns the role of astrocytes in neurodegeneration, notably in Alzheimer's disease, amyotrophic lateral sclerosis and AIDS-related dementia.

Memory disturbances and cognitive decline in Alzheimer's disease (AD) are currently believed to result from a defect in synaptic efficacy. DNF researchers have recently shown that astrocytes control the strength of synaptic connectivity in a cortico-hippocampal circuit involved in early AD by activity-dependent glutamate release. In addition, they find that this astrocytic mechanism is defective in the hippocampus of the PDAPP transgenic mouse, a model of AD, and they aim to investigate directly whether this defect contributes to synaptic dysfunction in AD. These studies are performed in living PDAPP mice using two-photon imaging in layers 2 and 3 of the cerebral cortex. Astrocytes in vivo are identified by a cell-selective stain and double-labeled with functional stains including calcium dyes. Alterations of astrocyte-neuron signalling are evaluated at different stages of AD progression, from stages of initial cognitive deficits preceding ß-amyloid plaque formation, to more advanced ones, when the mice display diffuse amyloid plaques - see Volterra.

Views on the causes of Amyotrophic Lateral Sclerosis (ALS), the fatal disease that causes degeneration of motor neurons innervating our skeletal muscles, have changed drastically in recent years. Studies in a transgenic model of ALS have revealed that the process by which the motor neurons die requires interactions with the surrounding glial cells. This has brought attention to the massive inflammatory glial reaction around spinal motor neurons and has led to the demonstration that microglial alterations contribute to the late phase of ALS. The role of astrocytes remains, in contrast, less clear. Researchers at the DBCM in collaboration with colleagues at the University of Milan are studying astrocytic abnormalities and the underlying mechanisms in mice carrying a mutated human gene coding for Cu-Zn superoxide dismutase (hSOD1G93A mice). With combined morphological, biochemical and behavioral analyses they aim to define the contribution of astrocytes to disease progression and to test new neuroprotective interventions based on the targeting of astrocytes - see Volterra

Another part of the studies focuses on the way in which astrocytes stimulated by a coat protein (gp120) of the AIDS virus (HIV-1) can kill neurons. DNF researchers have shown how this stimulation transforms a physiological signalling cascade into a neurotoxic one, by a negative interaction between astrocytes and microglia in which the cytokine TNFα plays a central role. They have also demonstrated that we can achieve neuroprotection in vivo by blocking this cascade. In view of the potential implication in several brain pathologies and of the consequent therapeutic interest, they are now studying in detail the molecular and cellular aspects of TNFα signalling in physiological and pathological astrocyte-neuron communication - see Volterra.

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