Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer's disease mouse model.

Astrocytic network alterations have been reported in Alzheimer's disease (AD), but the underlying pathways have remained undefined. Here we measure astrocytic calcium, cerebral blood flow and amyloid-ß plaques in vivo in a mouse model of AD using multiphoton microscopy. We find that astrocytic hyperactivity, consisting of single-cell transients and calcium waves, is most pronounced in reactive astrogliosis around plaques and is sometimes associated with local blood flow changes. We show that astroglial hyperactivity is reduced after P2 purinoreceptor blockade or nucleotide release through connexin hemichannels, but is augmented by increasing cortical ADP concentration. P2X receptor blockade has no effect, but inhibition of P2Y1 receptors, which are strongly expressed by reactive astrocytes surrounding plaques, completely normalizes astrocytic hyperactivity. Our data suggest that astroglial network dysfunction is mediated by purinergic signalling in reactive astrocytes, and that intervention aimed at P2Y1 receptors or hemichannel-mediated nucleotide release may help ameliorate network dysfunction in AD.

Long-term cerebral cortex protection and behavioral stabilization by gonadal steroid hormones after transient focal hypoxia.

Sex steroids are neuroprotective following traumatic brain injury or during neurodegenerative processes. In a recent short-term study, we have shown that 17ß-estradiol (E) and progesterone (P) applied directly after ischemia reduced the infarct volume by more than 70%. This protection might primarily result from the anti-inflammatory effects of steroids. Here, we focus on the long-term neuroprotection by both steroids with respect to the infarct volume, functional recovery, and vessel density in the penumbra. The application of E/P during the first 48h after stroke (transient middle cerebral artery occlusion, tMCAO) revealed neuroprotection after two weeks. The infarct area was reduced by 70% and motor activity was preserved compared to placebo-treated animals. Blood vessel density in the penumbra using immunohistochemistry for von Willebrand factor showed increased vessel density after tMCAO which was not affected by hormones. Expression of vascular endothelial growth factor (VEGF) and its receptor (R1) was increased at 24h after tMCAO and up-regulated by E/P but not changed 14 days after stroke. These findings suggest that the neuroprotective potency of both steroids is sustained and persists for at least two weeks. Besides anti-inflammatory and anti-apoptotic actions, angiogenesis in the damaged area appears to be initially affected early after ischemia and is manifested up to two weeks. This article is part of a Special Issue entitled 'Neurosteroids'.