In the brain, astrocytes provide metabolic and trophic support to neurones. Failure in executing astroglial homeostatic functions may contribute to the initiation and propagation of diseases, including Alzheimer disease (AD), characterized by a progressive loss of neurones over years. Here, we examined whether astrocytes from a mice model of AD isolated in the pre-symptomatic phase of the disease exhibit alterations in vesicle traffic, vesicular peptide release and purinergic calcium signalling. In cultured astrocytes isolated from a newborn wild-type (wt) and 3xTg-AD mouse, secretory vesicles and acidic endosomes/lysosomes were labelled by transfection with plasmid encoding atrial natriuretic peptide tagged with mutant green fluorescent protein (ANP.emd) and by LysoTracker, respectively. The intracellular Ca2+ concentration ([Ca2+]i) was monitored with Fluo-2 and visualized by confocal microscopy. In comparison with controls, spontaneous mobility of ANP- and LysoTracker-labelled vesicles was diminished in 3xTg-AD astrocytes; the track length (TL), maximal displacement (MD) and directionality index (DI) were all reduced in peptidergic vesicles and in endosomes/lysosomes (P<0.001), as was the ATP-evoked attenuation of vesicle mobility. Similar impairment of peptidergic vesicle trafficking was observed in wt rat astrocytes transfected to express mutated presenilin 1 (PS1M146V). The ATP-evoked ANP discharge from single vesicles was less efficient in 3xTg-AD and PS1M146V–expressing astrocytes than in respective wt controls (P<0.05). Purinergic stimulation evoked biphasic and oscillatory [Ca2+]i responses; the latter were less frequent (P<0.001) in 3xTg-AD astrocytes. Expression of PS1M146V in astrocytes impairs vesicle dynamics and reduces evoked secretion of the signalling molecule ANP; both may contribute to the development of AD.

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Oligodendrocytes are specialised glial cells that myelinate CNS axons. Myelinated axons are bundled together into white matter tracts that interconnect grey matter areas of the brain and are essential for rapid, integrated neuronal communication and cognitive function. Life-long generation of oligodendrocytes is required for myelination of new neuronal connections and repair of myelin lost through natural 'wear and tear'. This is the function of a substantial population of adult oligodendrocyte progenitors (OPs). Notably, there is white matter shrinkage and decreased myelination in the ageing brain, which is accelerated in dementia. The underlying causes of myelin loss in dementia are unresolved, but it implies a decline in the regenerative capacity of OPs. A feature of OPs is that they form neuron-glial synapses and respond to glutamate released by neurons via a range of glutamate receptors. Glutamate neurotransmission onto OPs is proposed to regulate their proliferation and differentiation into myelinating oligodendrocytes. Here, we discuss evidence that deregulation of glutamate neurotransmission in dementia and compromised generation of oligodendrocytes from OPs are key features of myelin loss and associated cognitive decline.