Alzheimer´s Disease (AD) is the world’s most common dementing illness. Deposition of amyloid beta peptide (Aβ) drives cerebral neuroinflammation by activating microglia1,2. Indeed, Aβ activation of the NLRP3 inflammasome in microglia is fundamental for IL-1β maturation and subsequent inflammatory events3. However, it remains unknown whether NLRP3 activation contributes to AD in vivo. Here, we demonstrate strongly enhanced active caspase-1 expression in human MCI and AD brains suggesting a role for the inflammasome in this neurodegenerative disease. NLRP3−/− or caspase-1−/− mice carrying mutations associated with familiar AD were largely protected from loss of spatial memory and other AD-associated sequelae and demonstrated reduced brain caspase-1 and IL-1β activation as well as enhanced Aβ clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of Aβ in the APP/PS1 model of Alzheimer’s disease. These results reveal an important role for the NLRP3 / caspase-1 axis in AD pathogenesis, and suggest that NLRP3 inflammasome inhibition represents a novel therapeutic intervention for AD.

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-β 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.

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD), but its role for disease initiation and progression has remained incompletely understood. We here show that the transcription factor Stat3 (signal transducer and activator of transcription 3), a canonical inducer of astrogliosis, is activated in an AD mouse model and human AD. Therefore, using a conditional knockout approach, we deleted Stat3 specifically in astrocytes in the APP/PS1 model of AD. We found that Stat3‐deficient APP/PS1 mice show decreased β‐amyloid levels and plaque burden. Plaque‐close microglia displayed a more complex morphology, internalized more β‐amyloid, and upregulated amyloid clearance pathways in Stat3‐deficient mice. Moreover, astrocyte‐specific Stat3‐deficient APP/PS1 mice showed decreased pro‐inflammatory cytokine activation and lower dystrophic neurite burden, and were largely protected from cerebral network imbalance. Finally, Stat3 deletion in astrocytes also strongly ameliorated spatial learning and memory decline in APP/PS1 mice. Importantly, these protective effects on network dysfunction and cognition were recapitulated in APP/PS1 mice systemically treated with a preclinical Stat3 inhibitor drug. In summary, our data implicate Stat3‐mediated astrogliosis as an important therapeutic target in AD.

This study identifies a GPCR, S1PR2, as a receptor for the Nogo-A-Δ20 domain of the membrane protein Nogo-A, which inhibits neuronal growth and synaptic plasticity.

Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and its proteolytic fragments are still poorly understood. Previously, we generated APPsa knock-in (KI) mice expressing solely the secreted ectodomain APPsa. Here, we generated double mutants (APPsa-DM) by crossing APPsa-KI mice onto an APLP2-deficient background and show that APPsa rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Surviving APPsa-DM mice exhibited impaired neuromuscular transmission, with reductions in quantal content, readily releasable pool, and ability to sustain vesicle release that resulted in muscular weakness. We show that these defects may be due to loss of an APP/Mint2/Munc18 complex. Moreover, APPsa-DM muscle showed fragmented postsynaptic specializations, suggesting impaired postnatal synaptic maturation and/or maintenance. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPsa-DM mice already showed pronounced hippocampal dysfunction, impaired spatial learning and a deficit in LTP that could be rescued by GABA A receptor inhibition. Collectively, our data show that APLP2 and APP are synergistically required to mediate neuromuscular transmission, spatial learning and synaptic plasticity.

Whereas the role of NogoA in limiting axonal fiber growth and regeneration following an injury of the mammalian central nervous system (CNS) is well known, its physiological functions in the mature uninjured CNS are less well characterized. NogoA is mainly expressed by oligodendrocytes, but also by subpopulations of neurons, in particular in plastic regions of the CNS, e.g., in the hippocampus where it is found at synaptic sites. We analyzed synaptic transmission as well as long-term synaptic plasticity (longterm potentiation, LTP) in the presence of function blocking antiNogoA or anti-Nogo receptor (NgR) antibodies and in NogoA KO mice. Whereas baseline synaptic transmission, short-term plasticity and long-term depression were not affected by either approach, long-term potentiation was significantly increased following NogoA or NgR1 neutralization. Synaptic potentiation thus seems to be restricted by NogoA. Surprisingly, synaptic weakening was not affected by interfering with NogoA signaling. Mechanistically of interest is the observation that by blockade of the GABA A receptors normal synaptic strengthening reoccurred in the absence of NogoA signaling. The present results show a unique role of NogoA expressed in the adult hippocampus in restricting physiological synaptic plasticity on a very fast time scale. NogoA could thus serve as an important negative regulator of functional and structural plasticity in mature neuronal networks.C hanges in the connectivity of neurons-synaptic plasticityregulate the fine-tuning of neuronal networks during development and during adult learning. Synaptic plasticity includes functional and structural modifications at neurons and may be the underlying mechanism for learning and memory processes (1). The storage of new information therefore might depend on ever changing neuronal networks. On the other hand, recent data indicate that the large scale organization of neuronal networks is kept remarkably stable to maintain a constant flow of information and to support long-term memory storage (reviewed in ref. 2).In the CA1 region of the hippocampus, changes in neuronal activity can lead to changes in synaptic weight. Molecular mechanisms include here changes in the number or properties of neurotransmitter receptors, retrograde messengers, structural changes at synapses, and activation of transcription/translation (3). What is less clear is whether molecular mechanisms restricting changes in synaptic weight and thus stabilizing the synapse also play a role as well. In this context it is interesting to note that preventing further potentiation of a given set of synapses in a neuronal network can be induced by a homeostatic shutdown of long-term potentiation (LTP) after intense stimulation (4). In the search for such molecular stabilizers, we investigated the protein NogoA, which has been identified as a negative regulator of structural changes in the CNS (5). NogoA prevents neurite outgrowth in the adult CNS after injury (6) and regulates the progressive restriction of plasticity dur...

Vascular cognitive impairment is the second most common form of dementia. The pathogenic pathways leading to vascular cognitive impairment remain unclear but clinical and experimental data have shown that chronic reactive astrogliosis occurs within white matter lesions, indicating that a sustained pro-inflammatory environment affecting the white matter may contribute towards disease progression. To model vascular cognitive impairment, we induced prolonged mild cerebral hypoperfusion in mice by bilateral common carotid artery stenosis. This chronic hypoperfusion resulted in reactive gliosis of astrocytes and microglia within white matter tracts, demyelination and axonal degeneration, consecutive spatial memory deficits, and loss of white matter integrity, as measured by ultra high-field magnetic resonance diffusion tensor imaging. White matter astrogliosis was accompanied by activation of the pro-inflammatory transcription factor nuclear factor (NF)-kB in reactive astrocytes. Using mice expressing a dominant negative inhibitor of NF-kB under the control of the astrocyte-specific glial fibrillary acid protein (GFAP) promoter (GFAP-IkBα-dn), we found that transgenic inhibition of astroglial NF-kB signaling ameliorated gliosis and axonal loss, maintained white matter structural integrity, and preserved memory function. Collectively, our results imply that pro-inflammatory changes in white matter astrocytes may represent an important detrimental component in the pathogenesis of vascular cognitive impairment, and that targeting these pathways may lead to novel therapeutic strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0350-3) contains supplementary material, which is available to authorized users.

Reichenbach et al. show that long-term P2Y1-receptor inhibition normalizes cerebral network dysfunction in an Alzheimer’s disease mouse model. This network recovery restores functional and structural synaptic integrity as well as learning and memory, establishing P2Y1-receptor inhibition as a novel potential treatment target.