Shah D, Gsell W, Wahis J, Luckett ES, Jamoulle T, Vermaercke B, Preman P, Moechars D, Hendrickx V, Jaspers T, Craessaerts K, Horré K, Wolfs L, Fiers M, Holt M, Thal DR, Callaerts-Vegh Z, D’Hooge R, Vandenberghe R, Himmelreich U, Bonin V, De Strooper B. Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer’s Disease. bioRxiv, April 26, 2022 bioRxiv

Recommends

Please login to recommend the paper.

Comments

  1. The authors provide compelling evidence for an interaction between neuronal and astrocytic dysfunction in early stages of Alzheimer’s disease and relate them to impairments of functional connectivity in mice and humans. These findings are especially relevant as they take a more integrated view of the neuro-glial circuits impaired in Alzheimer’s disease and take into account possible interactions between astrocytes and neurons.

    At early disease stages, plaques are not detectable but soluble Aβ levels are already elevated. We have previously demonstrated that Aβ dimers and/or oligomers cause an impairment of glutamate uptake via transporter proteins, which are predominantly located on astrocytic processes (Zott and Konnerth, 2022; Zott et al., 2019). The ensuing accumulation of extracellular glutamate at synapses triggers neuronal hyperactivation.

    This work by Shah et al. once more places astrocytes at the epicenter of early neuronal hyperactivity. Remarkably, the manipulation of astrocytic activity using DREADDs directly affected neuronal activity. However, the mechanism of astrocytic dysfunction in AD as well as the signaling pathway from astrocytes to neurons remain elusive. This highlights the importance to study astrocytes at early disease stages.

    Surprisingly, the authors found that astrocytic activity is downregulated in three month-old APP NL-F mice. Previously published work found no difference in astrocytic activity before (Kuchibhotla et al., 2009) and an increase in astrocytic Ca2+-transients after plaque formation (Delekate et al., 2014; Kuchibhotla et al., 2009; Reichenbach et al., 2018). However, these experiments were performed in different models and cortical regions. In consequence, longitudinal experiments to investigate the time course and spatial distribution of astrocytic dysfunctions will be crucial in the future.

    References:

    Delekate A, Füchtemeier M, Schumacher T, Ulbrich C, Foddis M, Petzold GC. Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer's disease mouse model. Nat Commun. 2014 Nov 19;5:5422. PubMed.

    Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science. 2009 Feb 27;323(5918):1211-5. PubMed.

    Reichenbach N, Delekate A, Breithausen B, Keppler K, Poll S, Schulte T, Peter J, Plescher M, Hansen JN, Blank N, Keller A, Fuhrmann M, Henneberger C, Halle A, Petzold GC. P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer's disease model. J Exp Med. 2018 Jun 4;215(6):1649-1663. Epub 2018 May 3 PubMed.

    Zott B, Konnerth A. Impairments of glutamatergic synaptic transmission in Alzheimer's disease. Semin Cell Dev Biol. 2022 Mar 22; PubMed.

    Zott B, Simon MM, Hong W, Unger F, Chen-Engerer HJ, Frosch MP, Sakmann B, Walsh DM, Konnerth A. A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science. 2019 Aug 9;365(6453):559-565. PubMed.

    View all comments by Benedikt Zott

  2. It has remained largely elusive if, when, and how astrocytes modulate the activity of neuronal networks on the micro- and mesoscale level. In previous publications, we and the Bacskai lab have demonstrated that reactive astrocytes around plaques in AD mouse models show increased calcium activity, and that this hyperactivity is to a large part mediated by purinoreceptor activation in the peri-plaque pro-inflammatory environment (Kuchibhotla et al., 2009; Delekate et al., 2014). Consequently, transgenic or pharmacological normalization of this hyperactive astroglial phenotype normalizes neuronal network activity and attenuates cognitive deficits (Reichenbach et al., 2018). This was confirmed in a recent study in awake-behaving APP/PS1 mice, which showed astroglial hyperactivity at the plaque-bearing stage under baseline conditions (Lines et al., 2022). 

    This paper extends these findings, and also generates new questions. First, using resting-state fMRI, the authors identify the cingulate cortex as a region of neuronal hyperactivity (based on increased functional connectivity) in humans and transgenic APPNL-F mice at the pre- or early plaque stage. They confirm this neuronal hyperactivity by calcium imaging of the cingulate cortex in the mouse model. Surprisingly, however, they find that this hyperactive neuronal phenotype is accompanied by astroglial calcium hypoactivity, rather than hyperactivity. Stimulating astrocytes using a Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic approach resulted in a normalization of neuronal activity, similar to what was shown for the reduction of astroglial hyperactivity at the plaque-bearing stage in other models (Reichenbach et al., 2018). Importantly, they also show that chemogenetic stimulation of astrocytes in wild-type mice increases neuronal network activity; however, if neuronal network activity is pharmacologically raised, the same chemogenetic astroglial intervention attenuates neuronal activity.

    This paper has several important implications. First, it confirms that brain areas of aberrant network activity identified by fMRI or other whole-brain imaging techniques display network changes at the cellular and subcellular level, and that astrocytes are centrally involved in these alterations. Second, the study confirms functional and morphological studies in humans that astrocytes are among the earliest responders to rising amyloid levels (Schöll et al., 2015). Third, it implies that astrocytes possess yet-to-be-identified homoeostatic mechanisms by which their activity can raise or attenuate neuronal synaptic activity in a context-dependent fashion.

    Importantly, it appears that stimulation of pre-plaque hypoactive astrocytes has a similar effect on neuronal networks as attenuation of plaque-stage hyperactive astrocytes, suggesting a “Goldilocks” zone of astroglial activity necessary for physiological synaptic function and perhaps normal behavior.

    On the other hand, the study raises a number of puzzling questions. First, it is now firmly established that neuroinflammation is one of the earliest steps of the pathological cascade in AD, and that astrocytes respond to, and perpetuate, this inflammation. Moreover, the abovementioned studies, in addition to models of other diseases, have shown that astrocytes typically become hyperactive under pro-inflammatory conditions. Why then would they be hypoactive at the pre-plaque stage? One possibility is that specific molecular pathways, such as ATP release and purinergic activation, only appear at the plaque-bearing stage and specifically in the peri-plaque region. It will therefore be important to measure astroglial and neuronal activity in the cingulate cortex, and ideally other regions, of older APPNL-F mice as well.

    Second, the data in the current paper were obtained in anesthetized mice, and most (if not all) anesthetics profoundly decrease astrocyte signaling (Thrane et al., 2012). Although astroglial hyperactivity persisted during anesthesia in other regions in AD models (Kuchibhotla et al., 2009; Delekate et al., 2014), it is currently unknown how sedation affects astrocytes within the cingulate cortex. Specifically, their behavior during anesthesia may differ from other cortical or subcortical regions studied previously, just as default-mode network activity differs from other networks during sleep or sedation (Heine et al., 2012). 

    Third, how can one mechanism—an increase in astrocytic calcium levels—raise or attenuate neuronal network activity in a context-dependent manner? The answer is currently unknown, but may be related to different inputs to, and molecules released from, astrocytes under these conditions. These remain to be identified in future studies employing single-cell transcriptomics, transgenic manipulation, and super-resolution imaging.

    Importantly, a better understanding of the molecular mechanisms governing the modulation of neuronal network activity by astrocytes may lead to the identification of novel symptomatic or perhaps causal treatment avenues for AD.

    References:

    Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science. 2009 Feb 27;323(5918):1211-5. PubMed.

    Delekate A, Füchtemeier M, Schumacher T, Ulbrich C, Foddis M, Petzold GC. Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer's disease mouse model. Nat Commun. 2014 Nov 19;5:5422. PubMed.

    Reichenbach N, Delekate A, Breithausen B, Keppler K, Poll S, Schulte T, Peter J, Plescher M, Hansen JN, Blank N, Keller A, Fuhrmann M, Henneberger C, Halle A, Petzold GC. P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer's disease model. J Exp Med. 2018 Jun 4;215(6):1649-1663. Epub 2018 May 3 PubMed.

    Lines J, Baraibar AM, Fang C, Martin ED, Aguilar J, Lee MK, Araque A, Kofuji P. Astrocyte-neuronal network interplay is disrupted in Alzheimer's disease mice. Glia. 2022 Feb;70(2):368-378. Epub 2021 Nov 2 PubMed.

    Reichenbach N, Delekate A, Breithausen B, Keppler K, Poll S, Schulte T, Peter J, Plescher M, Hansen JN, Blank N, Keller A, Fuhrmann M, Henneberger C, Halle A, Petzold GC. P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer's disease model. J Exp Med. 2018 Jun 4;215(6):1649-1663. Epub 2018 May 3 PubMed.

    Thrane AS, Rangroo Thrane V, Zeppenfeld D, Lou N, Xu Q, Nagelhus EA, Nedergaard M. General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex. Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):18974-9. Epub 2012 Oct 29 PubMed.

    Heine L, Soddu A, Gómez F, Vanhaudenhuyse A, Tshibanda L, Thonnard M, Charland-Verville V, Kirsch M, Laureys S, Demertzi A. Resting state networks and consciousness: alterations of multiple resting state network connectivity in physiological, pharmacological, and pathological consciousness States. Front Psychol. 2012;3:295. Epub 2012 Aug 27 PubMed.

    View all comments by Gabor Petzold

  3. Our results, and a recent paper from Lee et al. (2022), report a decrease of astrocyte calcium activity at early stages of amyloid pathology. This is in contrast with observations of increased calcium signaling reported in plaque-bearing mice (Kuchibhotla et al., 2009; Lines et al., 2022; Delekate et al., 2014). We argue that the decrease of astrocyte calcium signaling is a phenotype attributed to preplaque stages of the disease, recovery of which improves AD-related network disruptions. We highly recommend the preprint article at Cell Reports by Lee at al., who made similar observations independently in an APP/PS1 mouse model of amyloid pathology. That our findings are consistent across very different mouse models, and can be reproduced by independent research groups, indicates these results are robust and further emphasizes their importance.

    References:

    Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science. 2009 Feb 27;323(5918):1211-5. PubMed.

    Lines J, Baraibar AM, Fang C, Martin ED, Aguilar J, Lee MK, Araque A, Kofuji P. Astrocyte-neuronal network interplay is disrupted in Alzheimer's disease mice. Glia. 2022 Feb;70(2):368-378. Epub 2021 Nov 2 PubMed.

    Delekate A, Füchtemeier M, Schumacher T, Ulbrich C, Foddis M, Petzold GC. Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer's disease mouse model. Nat Commun. 2014 Nov 19;5:5422. PubMed.

    Lee YF, Russ AN, Zhao Q, Maci M, Miller MR, Hou SS, Algamal M, Araque A, Galea E, Bacskai BJ, Kastanenka K. Optogenetic Targeting of Astrocytes Restores Sleep-Dependent Brain Rhythm Function and Slows Alzheimer's Disease. Cell Reports, 8 Apr 2022 Cell Reports

    View all comments by Disha Shah

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Hyperconnectivity in Cingulate Precedes Amyloid. Astrocytes to Blame?