Activity-dependent translation dynamically alters the proteome of the perisynaptic astrocyte process

Sapkota, Darshan; Kater, Mandy S.J.; Sakers, Kristina; Nygaard, Kayla R; Liu, Yating; Koester, Sarah; Fass, Stuart B.; Lake, Allison M.; Khazanchi, Rohan; Khankan, Rana R.; Krawczyk, Mitchell C.; Smit, August B.; Maloney, Susan E.; Verheijen, Mark H. G.; Zhang, Ye; Dougherty, Joseph D.

doi:10.1016/j.celrep.2022.111474

Cited by 25 publications

(27 citation statements)

References 92 publications

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“…This was studied in both WT and APP/PS1 mice. The animals were sacrificed 4 h post-shock (delayed shock, DS), a timepoint for which we previously showed alterations in proteins expressed in PAPs upon fear memory consolidation ( Rao-Ruiz et al, 2015 ; Sapkota et al, 2022 ). We found impaired contextual fear memory present in APP/PS1 mice at the age of 3 months ( Figure 2A ) which is in line with earlier reports by our group ( Végh et al, 2014 ; Kater et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

“…The molecular mechanism underlying the growth or retraction of the PAP tip remains to be determined, but may involve actin binding proteins, such as Ezrin ( Badia-Soteras et al, 2022 ), Cofilin-1 ( Henneberger et al, 2020 ) or Profilin-1 ( Molotkov et al, 2013 ) and activity-induced translation of such proteins locally in the PAPs ( Sapkota et al, 2022 ). Importantly, these molecular processes seem to be impaired in APP/PS1 mice which do not show PAP retraction upon neuronal stimulation.…”

Section: Discussionmentioning

confidence: 99%

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Electron microscopy analysis of astrocyte-synapse interactions shows altered dynamics in an Alzheimer’s disease mouse model

Kater

Badia‐Soteras

Weering

et al. 2023

Front. Cell. Neurosci.

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IntroductionAstrocyte-synapse bi-directional communication is required for neuronal development and synaptic plasticity. Astrocytes structurally interact with synapses using their distal processes also known as leaflets or perisynaptic astrocytic processes (PAPs). We recently showed that these PAPs are retracted from hippocampal synapses, and involved in the consolidation of fear memory. However, whether astrocytic synaptic coverage is affected when memory is impaired is unknown.MethodsHere, we describe in detail an electron microscopy method that makes use of a large number of 2D images to investigate structural astrocyte-synapse interaction in paraformaldehyde fixed brain tissue of mice.Results and discussionWe show that fear memory-induced synaptic activation reduces the interaction between the PAPs and the presynapse, but not the postsynapse, accompanied by retraction of the PAP tip from the synaptic cleft. Interestingly, this retraction is absent in the APP/PS1 mouse model of Alzheimer’s disease, supporting the concept that alterations in astrocyte-synapse coverage contribute to memory processing.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Electron microscopy analysis of astrocyte-synapse interactions shows altered dynamics in an Alzheimer’s disease mouse model

Kater

Badia‐Soteras

Weering

et al. 2023

Front. Cell. Neurosci.

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“…Astrocytes participate in the encoding of memory stimulated after neuronal activity [ 3 ], and sAPPα signaling may play a part in this role. The regulation of translation in astrocytes by neuronal activity is also proposed to be a mechanism by which astrocytes modulate nervous system functioning [ 63 , 64 ]. Astrocytes modulate synaptic function by secreting neurotrophic factors, controlling synaptic formation [ 65 ] and regulating the concentration of neurotransmitters at the synapses [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

Secreted Amyloid Precursor Protein Alpha (sAPPα) Regulates the Cellular Proteome and Secretome of Mouse Primary Astrocytes

Peppercorn

Kleffmann

Hughes

et al. 2023

IJMS

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Secreted amyloid precursor protein alpha (sAPPα), processed from a parent mammalian brain protein, amyloid precursor protein, can modulate learning and memory. Recently it has been shown to modulate the transcriptome and proteome of human neurons, including proteins with neurological functions. Here, we analysed whether the acute administration of sAPPα facilitated changes in the proteome and secretome of mouse primary astrocytes in culture. Astrocytes contribute to the neuronal processes of neurogenesis, synaptogenesis and synaptic plasticity. Cortical mouse astrocytes in culture were exposed to 1 nM sAPPα, and changes in both the whole-cell proteome (2 h) and the secretome (6 h) were identified with Sequential Window Acquisition of All Theoretical Fragment Ion Spectra–Mass Spectrometry (SWATH-MS). Differentially regulated proteins were identified in both the cellular proteome and secretome that are involved with neurologically related functions of the normal physiology of the brain and central nervous system. Groups of proteins have a relationship to APP and have roles in the modulation of cell morphology, vesicle dynamics and the myelin sheath. Some are related to pathways containing proteins whose genes have been previously implicated in Alzheimer’s disease (AD). The secretome is also enriched in proteins related to Insulin Growth Factor 2 (IGF2) signaling and the extracellular matrix (ECM). There is the promise that a more specific investigation of these proteins will help to understand the mechanisms of how sAPPα signaling affects memory formation.

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“…However, recent work, combining use of astrocyte-specific TRAP with subcellular fractionation, has allowed the purification of ribosomes from astrocyte peripheral processes associated with synapses (synaptosomes), strongly suggesting the possibility of local translation in astrocytes [63]. Furthermore, this local translatome appears to be dynamic and capable of modification by neuronal activity [64,65]. In mice, translation of new proteins appears to drive, at least in part, the proteomic changes that occur in peripheral astrocyte processes following exposure to a fear conditioning paradigm [65], with the resultant behavioral modifications presumably arising due to changes in astrocyte-neuron interactions which impact circuit activity.…”

Section: Transcriptome/proteomementioning

confidence: 99%

“…Furthermore, this local translatome appears to be dynamic and capable of modification by neuronal activity [64,65]. In mice, translation of new proteins appears to drive, at least in part, the proteomic changes that occur in peripheral astrocyte processes following exposure to a fear conditioning paradigm [65], with the resultant behavioral modifications presumably arising due to changes in astrocyte-neuron interactions which impact circuit activity. In addition, local protein trafficking appears to play a role in defining the composition of the astrocyte process, in response to neuronal activity.…”

Section: Transcriptome/proteomementioning

confidence: 99%

Astrocyte heterogeneity and interactions with local neural circuits

Holt

2023

Essays in Biochemistry

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Astrocytes are ubiquitous within the central nervous system (CNS). These cells possess many individual processes which extend out into the neuropil, where they interact with a variety of other cell types, including neurons at synapses. Astrocytes are now known to be active players in all aspects of the synaptic life cycle, including synapse formation and elimination, synapse maturation, maintenance of synaptic homeostasis and modulation of synaptic transmission. Traditionally, astrocytes have been studied as a homogeneous group of cells. However, recent studies have uncovered a surprising degree of heterogeneity in their development and function, suggesting that astrocytes may be matched to neurons to support local circuits. Hence, a better understanding of astrocyte heterogeneity and its implications are needed to understand brain function.

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Activity-dependent translation dynamically alters the proteome of the perisynaptic astrocyte process

Cited by 25 publications

References 92 publications

Electron microscopy analysis of astrocyte-synapse interactions shows altered dynamics in an Alzheimer’s disease mouse model

Electron microscopy analysis of astrocyte-synapse interactions shows altered dynamics in an Alzheimer’s disease mouse model

Secreted Amyloid Precursor Protein Alpha (sAPPα) Regulates the Cellular Proteome and Secretome of Mouse Primary Astrocytes

Astrocyte heterogeneity and interactions with local neural circuits

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