Reactive astrocytes A1/A2, (Li, 2019 #2281) molecular-expression table, PD and astrocyte, PET for astrocyte [11C]BU99008, aSyn animal models Non-Spreading + PD mouse models in QPS Line 61
Reactive astrocytes (small summary)
| A1 | NF-kB | Release IFN-r, C1q, Len2 | Neurodegeneration |
| A2 | STAT3 | Release neurotrophic factors (BDNF, VEGF, Bfgf) | neuroprotection |
Reactive astrocytes — Below (Li, 2019 #2281)
| Reactive astrocytes | Molecular expression | Refs | |
|---|---|---|---|
| A1 astrocytes | Up regulation | Inflammatory signaling through NF-κB | [105, ..] |
| Glutamate and ATP release | [107, ..] | ||
| Inflammatory mediators secretion (prostaglandinD2, IFN-γ, and TGF-β) | [93, 10..] | ||
| Lcn2 secretion | [110] | ||
| IL-1α, C1q, TNF | [9, 10..] | ||
| A1 | Down regulation | GPC4, GPC6, SPARCL1 expression | [111, ..] |
| Excitatory amino acid transporter 2 (EAAT2), Glutamate transporter 1 (GLT1) | [113, ..] | ||
| Trophic factor release | [9, 1..] | ||
| Lactate transportation | [85] | ||
| GABA release through GAT-3 | [116] | ||
| A2 astrocytes | Up regulation | Inflammatory signaling through STAT3 | [27, ..] |
| Thrombospondins (THBS1 and THBS2) | [33] | ||
| Aquaporin-4 | [34] | ||
| HMGB1 and β-2 integrin | [35] | ||
| Trophic factor release (BDNF, VEGF and bFGF) | [9, ..] | ||
| A2 | Down regulation | H2-D1, Gbp2, Fkbp5, Srgn | [10..] |
PD and astrocyte
| content | |
|---|---|
| (Li, 2019 #2281) | Astrocyte reactivity is detected in the SN pars compacta (SNpc) of patients with PD[76]. At the time of PD initiation, a-syn accumulated in astrocytes |
| Pathological examinations of PD brains show an increased number of astrocytes as well as an elevated level of GFAP expression [78]. | |
| Pathological studies also found that astrocytes can be activated and accumulated with nonfibrillized α-syn at early stages of PD brain, which distributed more broadly than Lewy bodies [79 | |
| activation of STAT3 signaling pathway in astrocytes seems to be a consistent feature in PD. 이건 neuroprotective effect 일텐데 |
PET for astrocyte
[11C]BU99008
Astrocyte Activation as a Novel Marker of Disease Progression in Parkinson’s Disease: A PET Imaging Study
Study Rationale: Brain inflammation, regulated by cells called microglia and astrocytes, has been shown to play a role in the initiation and progression of Parkinson’s disease. However, the role of astrocyte cells in the earliest disease stages (i.e., before the onset of movement symptoms) and how astrocytes contribute to disease progression is not fully understood.
Hypothesis: Changes in astrocytes could play a role in disease onset and could contribute to the progression of Parkinson’s disease.
Study Design: We will use a technology called positron emission tomography (PET) that enables us to measure the activation of astrocytes in living patients using a novel radiotracer called [11C]BU99008. In this longitudinal study, the level of astrocyte activation will be compared across groups of (i) people with Parkinson’s-linked genetic mutations who have not yet shown movement symptoms, (ii) people with Parkinson’s from an unknown cause and (iii) control individuals at two time points (baseline and 12-month follow-up). This will allow us to investigate changes in astrocyte activation over time and the role of astrocytes in disease progression.
Impact on Diagnosis/Treatment of Parkinson’s Disease: This study could help to validate changles in astrocyte levels, measured in living patients with [11C]BU99008 PET, as a biomarker for disease onset and to monitor disease progression from premotor stages of Parkinson’s. Furthermore, our findings could open opportunities for the development of novel therapeutic interventions targeting astrocytes.
Researchers: Marios Politis, MD, MSc, PhD, FRCP, FEA
aSyn
Animal models of aSyn
Non-Spreading Models
다른 의견: These include transgenic mice (KO and overexpression), grafting models, intracerebral protein injections, or virally induced expression of α-syn. The main handicap of these models is that no significant nigrostriatal degeneration has been found in most of them, although some of these mice showed decreased striatal levels of TH or DA and behavioral impairments [80].
위 아래대표로 정리되는데 각각 채워질 어렵네.
(Rockenstein et al., 2002; Fleming et al.,2004; Hallett et al., 2012) Both wild-type and mutant a-syns have potential to form abnormal inclusions resembling Lewy bodies. (2010 Tanji Acta Neuropathol (2010) 120:145-154)
an age-dependent loss of SNc DA neurons preceded by early deficits in DA release from terminals in the dorsal striatum, protein aggregation, and reduced firing of SNc DA neurons [Janezic 104]
nigral DA neurons, progressive motor decrease, and cognitive impairment, but there is no fibrillary inclusion
| line | Promoter | Human SNCA gene | Rodent SNCA gene | |
|---|---|---|---|---|
| PDNG78 | PDGF promoter |
- Human WT alpha-syn-GFP Tg mouse under control PDGF promoter. - accumulation of GFP tagged ASYN in retinal ganglion cells, and that this accumulation of ASYN persisted in the same cells over time and increased with age (2018 Price) | ||
| (Thy-1-α-Syn) Line61 | murine Thy-1 promoter |
- overexpresses wild-type human ASYN under the murine Thy-1 promoter (Rockenstein et al. 2016, PMID 27126635) - (2018 Price) develops extensive accumulation of ASYN in areas relevant to PD11-13, neurodegeneration (including loss of TH immunoreactivity in the striatum14, inflammation7,11,15, and both motor and non-motor functional deficits16,17. Behavioral evaluations for 3 month efficacy studies in Line 61 transgenic. - (AC Immune DD A.2 presentations) no accumulation of insoluble a-Syn, no aS129 aSyn, no This aggregate, - harbor WT alleles of Gba1 - GBA activity: not different from WT (Rockenstein et al. 2016, PMID 27126635) - (Chesselet et al. 2012, PMID 22350713) alpha-syn, detected with an antibody that recognizes both mouse and human proteins, was overexpressed to a moderate degree (1.5- to 3.4-fold) in most brain regions examined in Thy1-aSyn mice compared to their wildtype littermates, with a higher (6.5-fold) over-expression in the thalamus (Table 1). |
Proteinase K Resistant Alpha-Syn Aggregates are Present in the Brain of Thy1-aSyn Mice, Thy1-aSyn Mice Show High Levels of 129S-Phosphorylated Alpha-Syn [neurodegeneration]
| |
| WT | SNCA BAC tg mouse | (Yamakado, 2012 #1460) (harboring 8 copies of the entire human α-syn gene and its gene expression regulatory regions) | ||
| wt 일컬 | Nussbaum Snca-; PAC-Tg(SNCAWT) JAX 010710 | Entire human SNCA gene (driven by the human SNCA promoter). Line was crossed with Snca KO to remove endogenous murine aSyn. Integration site unknown. | ||
| transgenic mice | Promoter: human PDGF-β promoter |
- Lewy bodies - NEUROdegeneration 보인다고 함. |
PD mouse models in QPS (Line 61) — Takeda info card
Line 61 mice express the human α-synuclein cDNA under the regulatory control of the murine Thy-1 promoter mainly in neurons. Animals are bred on a B6D2F1/J BcclHsd background. The transgene is about 10-fold higher expressed than the endogenous α-synuclein. If males and females respond differently, results shown below are from males only.
α-synuclein levels by MSD: The soluble and insoluble α-syn protein expression in the hippocampus of Line 61 mice increase over age as shown (Fig. 1A,B). In the striatum, the soluble α-syn protein decrease over age, while the insoluble α-syn protein does not significantly change (Fig. 1C,D).
Figure panel labels:
- A — Hippocampus Soluble (pg/μg/mg protein); x-axis: age in months
- B — Hippocampus Insoluble (pg/μg/mg protein); x-axis: age in months
- C — Striatum Soluble
- D — Striatum Insoluble
Figure 1 caption: α-synuclein protein expression levels in the soluble and insoluble fractions of the hippocampus and striatum of 2, 3, and 6 month old Line 61 mice. MSD-ISA. One-way ANOVA with Bonferroni’s post hoc test. *p<0.05, **p<0.01, ***p<0.001.
Footer: 5 |GBA GT PJ Meeting | 2020/04/14 | Confidential - for internal use only
Conditional Expression of Mutant α-Syn
- {Lin, 2012 #2241}
- Conditional Expression of Parkinson’s Disease-Related Mutant α-Syn
- tetracycline-regulated inducible transgenic mice that overexpressed the PD-related α-Syn A53T missense mutation in the mDA neurons
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Reactive astrocytes / Refs column | reference numbers like [105, ..], [107, ..], [93, 10..] | reads as written; the trailing reference numbers are partly clipped at the right edge and preserved with .. placeholders. |