Publications
19 results found
Matthews P, 2024, A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease, Nature Communications
Huang HX, Inglese P, Tang J, et al., 2024, Mass spectrometry imaging highlights dynamic patterns of lipid co-expression with Aβ plaques in mouse and human brains., J Neurochem
Lipids play crucial roles in the susceptibility and brain cellular responses to Alzheimer's disease (AD) and are increasingly considered potential soluble biomarkers in cerebrospinal fluid (CSF) and plasma. To delineate the pathological correlations of distinct lipid species, we conducted a comprehensive characterization of both spatially localized and global differences in brain lipid composition in AppNL-G-F mice with spatial and bulk mass spectrometry lipidomic profiling, using human amyloid-expressing (h-Aβ) and WT mouse brains controls. We observed age-dependent increases in lysophospholipids, bis(monoacylglycerol) phosphates, and phosphatidylglycerols around Aβ plaques in AppNL-G-F mice. Immunohistology-based co-localization identified associations between focal pro-inflammatory lipids, glial activation, and autophagic flux disruption. Likewise, in human donors with varying Braak stages, similar studies of cortical sections revealed co-expression of lysophospholipids and ceramides around Aβ plaques in AD (Braak stage V/VI) but not in earlier Braak stage controls. Our findings in mice provide evidence of temporally and spatially heterogeneous differences in lipid composition as local and global Aβ-related pathologies evolve. Observing similar lipidomic changes associated with pathological Aβ plaques in human AD tissue provides a foundation for understanding differences in CSF lipids with reported clinical stage or disease severity.
Melgosa-Ecenarro L, Doostdar N, Radulescu CI, et al., 2023, Pinpointing the locus of GABAergic vulnerability in Alzheimer?s disease, SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, Vol: 139, Pages: 35-54, ISSN: 1084-9521
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- Citations: 3
Canty AJ, Jackson JS, Huang L, et al., 2020, In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration, BMC Biology, Vol: 18
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Despite the widespread occurrence of axon and synaptic loss in the injured and diseased nervous system, the cellular and molecular mechanisms of these key degenerative processes remain incompletely understood. Wallerian degeneration (WD) is a tightly regulated form of axon loss after injury, which has been intensively studied in large myelinated fibre tracts of the spinal cord, optic nerve and peripheral nervous system (PNS). Fewer studies, however, have focused on WD in the complex neuronal circuits of the mammalian brain, and these were mainly based on conventional endpoint histological methods. Post-mortem analysis, however, cannot capture the exact sequence of events nor can it evaluate the influence of elaborated arborisation and synaptic architecture on the degeneration process, due to the non-synchronous and variable nature of WD across individual axons.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>To gain a comprehensive picture of the spatiotemporal dynamics and synaptic mechanisms of WD in the nervous system, we identify the factors that regulate WD within the mouse cerebral cortex. We combined single-axon-resolution multiphoton imaging with laser microsurgery through a cranial window and a fluorescent membrane reporter. Longitudinal imaging of > 150 individually injured excitatory cortical axons revealed a threshold length below which injured axons consistently underwent a rapid-onset form of WD (roWD). roWD started on average 20 times earlier and was executed 3 times slower than WD described in other regions of the nervous system. Cortical axon WD and roWD were dependent on synaptic density, but independent of axon complexity. Finally, pharmacological and genetic manipulations showed t
Canty A, Jackson J, Huang L, et al., 2020, In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration, BMC Biology, ISSN: 1741-7007
Background Despite the widespread occurrence of axon and synaptic loss in the injured and diseased nervous system, the cellular and molecular mechanisms of these key degenerative processes remain incompletely understood. Wallerian degeneration (WD) is a tightly regulated form of axon loss after injury, which has been intensively studied in large myelinated fibre tracts of the spinal cord, optic nerve and peripheral nervous system (PNS). Fewer studies, however, have focused on WD in the complex neuronal circuits of the mammalian brain, and these were mainly based on conventional endpoint histological methods. Post-mortem analysis, however, cannot capture the exact sequence of events nor can it evaluate the influence of elaborated arborization and synaptic architecture on the degeneration process, due to the non-synchronous and variable nature of WD across individual axons. Results To gain a comprehensive picture of the spatiotemporal dynamics and synaptic mechanisms of WD in the nervous system, we identify the factors that regulate WD within the mouse cerebral cortex. We combined single-axon-resolution multiphoton imaging with laser microsurgery through a cranial window and a fluorescent membrane reporter. Longitudinal imaging of > 150 individually injured excitatory cortical axons revealed a threshold length below which injured axons consistently underwent a rapid-onset form of WD (roWD). roWD started 10 times earlier and was executed 4 times slower than WD described in other regions of the nervous system. Cortical axon WD and roWD were dependent on synaptic density, but independent of axon complexity. Finally, pharmacological and genetic manipulations showed that a Nicotinamide Adenine Dinucleotide (NAD+)-dependent pathway could delay cortical roWD independent of transcription in the damaged neurons, demonstrating further conservation of the molecular mechanisms controlling WD in different areas of the mammalian nervous system. Conclusions Our data highlight the
Stephen T, Tamagnin F, Piegsa J, et al., 2019, Imbalance in the response of pre- and post-synaptic components to amyloidopathy, Scientific Reports, Vol: 9, ISSN: 2045-2322
Alzheimer’s disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Amyloid β (Aβ) species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aβ plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aβ plaques grow faster in the earlier stages of the disease and if their initial area is > 500 μm2; this may be due to deposition occurring in the plaque cloud. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre- but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the nderlying pathology, need to address changes in synapse dynamics.
Jackson J, Jambrina E, Li J, et al., 2019, Targeting the Synapse in Alzheimer’s Disease, Frontiers in Neuroscience, Vol: 13
Jackson JS, Witton J, Johnson JD, et al., 2017, Altered synapse stability in the early stages of tauopathy, Cell Reports, Vol: 18, Pages: 3063-3068, ISSN: 2211-1247
Synapse loss is a key feature of dementia, but it is unclear whether synaptic dysfunction precedes degenerative phases of the disease. Here, we show that even before any decrease in synapse density, there is abnormal turnover of cortical axonal boutons and dendritic spines in a mouse model of tauopathy-associated dementia. Strikingly, tauopathy drives a mismatch in synapse turnover; postsynaptic spines turn over more rapidly, whereas presynaptic boutons are stabilized. This imbalance between pre- and post-synaptic stability coincides with reduced synaptically driven neuronal activity in pre-degenerative stages of the disease.
Jackson J, 2016, IC‐P‐032: <i>In Vivo</i> Two‐Photon Imaging of The Effects of Tauopathy And Amyloidopathy on Synapse Dynamics in The Rtg4510 and J20 Transgenic Models Respectively, Alzheimer's & Dementia, Vol: 12, ISSN: 1552-5260
Jackson J, Canty AJ, Huang L, et al., 2015, Laser-Mediated Microlesions in Mouse Neocortex to Investigate Neuronal Degeneration and Regeneration., Curr Protoc Neurosci, Vol: 73, Pages: 2.24.1-2.24.17
In vivo two-photon (2P) imaging enables neural circuitry to be repeatedly visualized in both normal conditions and following trauma. This protocol describes how laser-mediated neuronal microlesions can be created in the cerebral cortex using an ultrafast laser without causing a significant inflammatory reaction or compromising the blood-brain barrier. Furthermore, directives are provided for the acute and chronic in vivo imaging of the lesion site, as well as for post-hoc analysis of the lesion site in fixed tissue, which can be correlated with the live imaging phase.
Avdic U, Chugh D, Osman H, et al., 2015, Absence of interleukin-1 receptor 1 increases excitatory and inhibitory scaffolding protein expression and microglial activation in the adult mouse hippocampus, Cellular and Molecular Immunology, Vol: 12, Pages: 645-647, ISSN: 1672-7681
Canty AJ, Huang L, Jackson J, et al., 2013, In-vivo single neuron axotomy triggers axon regeneration to restore synaptic density in specific cortical circuits, Nature Communications
Canty, Teles-Grilo Ruivo, Nesarajah, et al., 2013, Synaptic elimination and protection after minimal injury depend on cell type and their pre-lesion structural dynamics in the adult cerebral cortex., Journal of Neuroscience
Jackson J, Chugh D, Nilsson P, et al., 2012, Altered synaptic properties during integration of adult-born hippocampal neurons following a seizure insult, PLoS One, Vol: 7, Pages: 1-13, ISSN: 1932-6203
Pathological conditions affect several stages of neurogenesis in the adult brain, including proliferation, survival, cell fate, migration, and functional integration. Here we explored how a pathological environment modulates the heterogeneous afferent synaptic input that shapes the functional properties of newly formed neurons. We analyzed the expression of adhesion molecules and other synaptic proteins on adult-born hippocampal neurons formed after electrically-induced partial status epilepticus (pSE). New cells were labeled with a GFP-retroviral vector one week after pSE. One and three weeks thereafter, synaptic proteins were present on dendritic spines and shafts, but without differences between pSE and control group. In contrast, at six weeks, we found fewer dendritic spines and decreased expression of the scaffolding protein PSD-95 on spines, without changes in expression of the adhesion molecules N-cadherin or neuroligin-1, primarily located at excitatory synapses. Moreover, we detected an increased expression of the inhibitory scaffolding protein gephyrin in newborn but not mature neurons after SE. However, this increase was not accompanied by a difference in GABA expression, and there was even a region-specific decrease in the adhesion molecule neuroligin-2 expression, both in newborn and mature neurons. Neuroligin-2 clusters co-localized with presynaptic cholecystokinin terminals, which were also reduced. The expression of neuroligin-4 and glycine receptor was unchanged. Increased postsynaptic clustering of gephyrin, without an accompanying increase in GABAergic input or neuroligin-2 and -4 expression, the latter important for clustering of GABAA and glycine receptors, respectively, could imply an increased but altered inhibitory connectivity specific for newborn neurons. The changes were transient and expression of both gephyrin and NL-2 was normalized 3 months post-SE. Our findings indicate that seizure-induced brain pathology alters the sub-cellular expr
Wood JC, Jackson JS, Jakubs K, et al., 2011, Functional integration of new hippocampal neurons following insults to the adult brain is determined by characteristics of pathological environment, EXPERIMENTAL NEUROLOGY, Vol: 229, Pages: 484-493, ISSN: 0014-4886
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- Citations: 43
Jackson JS, Golding JP, Chapon C, et al., 2010, Homing of stem cells to sites of inflammatory brain injury after intracerebral and intravenous administration: a longitudinal imaging study, Stem Cell Research and Therapy, Vol: 1, ISSN: 1757-6512
IntroductionThis study aimed to determine the homing potential and fate of epidermal neural crest stem cells (eNCSCs) derived from hair follicles, and bone marrow-derived stem cells (BMSCs) of mesenchymal origin, in a lipopolysaccharide (LPS)-induced inflammatory lesion model in the rat brain. Both eNCSCs and BMSCs are easily accessible from adult tissues by using minimally invasive procedures and can differentiate into a variety of neuroglial lineages. Thus, these cells have the potential to be used in autologous cell-replacement therapies, minimizing immune rejection, and engineered to secrete a variety of molecules.MethodsBoth eNCSCs and BMSCs were prelabeled with iron-oxide nanoparticles (IO-TAT-FITC) and implanted either onto the corpus callosum in healthy or LPS-lesioned animals or intravenously into lesioned animals. Both cell types were tracked longitudinally in vivo by using magnetic resonance imaging (MRI) for up to 30 days and confirmed by postmortem immunohistochemistry.ResultsTransplanted cells in nonlesioned animals remained localized along the corpus callosum. Cells implanted distally from an LPS lesion (either intracerebrally or intravenously) migrated only toward the lesion, as seen by the localized MRI signal void. Fluorescence microscopy of the FITC tag on the nanoparticles confirmed the in vivo MRI data,ConclusionsThis study demonstrated that both cell types can be tracked in vivo by using noninvasive MRI and have pathotropic properties toward an inflammatory lesion in the brain. As these cells differentiate into the glial phenotype and are derived from adult tissues, they offer a viable alternative autologous stem cell source and gene-targeting potential for neurodegenerative and demyelinating pathologies.
Jackson J, Chapon C, Jones W, et al., 2009, <i>In vivo</i> multimodal imaging of stem cell transplantation in a rodent model of Parkinson's disease, JOURNAL OF NEUROSCIENCE METHODS, Vol: 183, Pages: 141-148, ISSN: 0165-0270
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- Citations: 21
Chapon C, Jackson JS, Aboagye EO, et al., 2009, An In Vivo Multimodal Imaging Study Using MRI and PET of Stem Cell Transplantation after Myocardial Infarction in Rats, MOLECULAR IMAGING AND BIOLOGY, Vol: 11, Pages: 31-38, ISSN: 1536-1632
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- Citations: 42
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