Gut-brain axis in NDDs Flashcards
Synucleionpathies
Group of neurodegenerative
diseases characterised by the accumulation of
insoluble α-synuclein (αSyn) protein in selectively
vulnerable populations of neurons (Lewy
bodies/neurites) and glia (glial cytoplasmic inclusions).
what type of synucleiopathy is AD
tauopathies
Describe PD?
- Neurological Disorder: Parkinson’s disease (PD) is a
progressive neurodegenerative disorder that primarily
affects movement due to the loss of dopamine-producing
neurons in the brain. - Symptoms: Common symptoms include tremors, stiffness,
bradykinesia (slowness of movement), and postural
instability. Non-motor symptoms include cognitive
impairment and mood disorders. - Prevalence: Approximately 10 million people worldwide
are affected by Parkinson’s disease, with incidence
increasing with age
Describe Lewy body
Lewy bodies are found in Parkinson’s
Disease, Parkinson’s Disease
Dementia, Dementia with Lewy Bodies
and Multiple system Atrophy, as well as
50% of Alzheimer’s disease cases
The neuropathologic hallmarks in
synucleinopathies are the presence of
Lewy bodies/neurites, intracellular
protein inclusions in the
somata/processes of a neuron
5 point mutations (A30P, E46K, H50Q,
G51D, A53T) associated with early
onset (>85% penetrance) of DLB, PDD
and PD
Describe the prion like spread of PD? and other NDDs (research this)
“Prion-like” spreading of αSyn pathology
What are the structural and fucntional charaterisation of the two alpha-syn strains
Bousset et al.2013 Two polymorphs of α-synuclein.
the two strains have different structures, levels of toxicity, and in vitro and in vivo seeding and propagation properties. Such strain differences may account for differences in disease progression in different individuals/cell types and/or types of synucleinopathies.
How is PD therorised to spread through the brain
when Braak (married couple) looked at the brains PD paitents at different stages/severity, they saw a spread beginning from the brain stem- midbrain-caudal to rostral spread through brain with major death todopaminergic neruons in the dopamine in niagra
What was Braaks through of PD spread?
They saw it beginning from the brain stem region so hypothesised that it might to do with origin in the body- the gut brain axis via the (parasymapthetic) ENS and vagus nerve
What was bartels model study using gut macrophages by ENS-directed injection of a-syn to study PD?
a-syn from healthy versus PD paitent.
ENS microinjection into duodenum of mice, and follow diease course.
Found it capitulates pathology fairly well. Cuases neurodegeration of substanita nigra so selectivity affects the same cells as a human PD paitent
What is the alternative ‘3K’ tetramer abrogating model?
using this mouse model- also recapitulates PD well, is reactive towards L-DOPA and substantia nigra neruodegenration.
This one also have lewy bodies and lipid a-syn clusters
Describe findings from the dysfunctional ENS in a-syn transgenic model-using spatial transcriptomics
Slide 15
Intresting as it has something to do with lyosomoes not being dysregualted in the neruons but in the macrophages- surprising find!
Proteomics on ENS-gMACs in a-syn model
gut Macrophages separated out from mouse model of PD. Mass spec conducted and found upregulational of lyosomal genes and PD risk genes like CTSD, rap7..
What is the Importance of Gut Macrophages for Neuronal Health in the ENS?
Neuronal Support & Protection
- Gut macrophages regulate inflammation and protect
enteric neurons.
- Clear cellular debris, preventing neurotoxic buildup.
Microbiome & Immune Balance
- Interact with gut microbiota to maintain
homeostasis.
- Prevent excessive immune responses that could
harm neurons.
Neurotransmission & Motility
- Support neurotransmitter balance, ensuring proper
gut motility.
- Influence the health of enteric glial cells, which
support neurons
What is the hypothesis for the role of the macrpophage in PD?
lyosomes within macropahes may be distating https://pubmed.ncbi.nlm.nih.gov/33004513/ read*
ENS-gMacs show lysosomal accumulation upon engulfment
of phosphorylated αSyn
phenotype recapitulated in ENS injection model.
Comapred to wild type macrophages in the ENS, the 3KL mouse model with phosphorylated a-syn shows increased lyosomal engulfmant and higher LAMP1 volume (?) https://pubmed.ncbi.nlm.nih.gov/36361864/
Link between prion and a-syn misfolded aggregtaes in CSF - recent advance in seeded amplification assay (SAA)
They wanted to develop a biochemical biomarker of PD. This would be the very first biomarker of synucleopathies!!
ENS-gMacs engulf α-Syn to potentially modulate its pathological prion-like
activity- explain this and the hypothesis generated
the used the SAA on gut macrophages they isolated from the ENS of 3KL(PD mouse model). They found prion active a-syn in the gut macropahges and none in the enteric neurons. So for prion a-syn that is pysiologically produced by the enteric neruons, it does not want it so the macropages end up sucking it all up.
What is the link between macrophages and immune cells
Role of T cells in PD- studies show T cells in those with PD react to a-syn whereas healthy people do not.
They found ENS-gMacs potentially activate T-cells in the presence of α-Syn pathology. CD3 T-cells
T-cells are in close proximity to the macrophages- they found this using micropsy
CD4+ T-cell activation upon injection of PD aSyn versus HC aSyn-using FACs.
research this.
Investigating T cells presence in the brain -using FACs and mouse model
T cells expand in the ENS and travel to the CNS in body-first PD.
Muscularis Mϕ possibly imprint Th17 cells via TGFβ1 in the presence of αsynucleinopathy- explain this
They screened for inflammatory markers.
Marker TBFB1 was revealed to …..?
Depletion of muscularis Mϕ using targeted αCSF1R injection-explain
Depletion of ENS-gut macrophages using targeted aCSF1R injection
impairs CD4+ T-cell activation upon αSyn PD treatment
macrophages call in the T cells after digesting a-syn.
Depletion of muscularis Mϕ ameliorates αS pathology and prevents T-cell expansion in the brainstem and midbrain
Peripheral macrophages & T-cells modify SNpc DA neurodegeneration
looking at cell death here. In gut macrophage knowckout, you do not see the a-syn causing cell death in the animals compared to controls.
Depletion of muscularis Mϕ improves motor behaviour
using rotarod beahvioural assay
Implicaiton of research for diagnosis
Early PD might be detected in the blood. Either by
inflammatory markers, αSyn aggregates, or specific Tcell populations
* Blood diagnostics are more feasible and cheaper to do
as regular screening – allowing risk altering drugs to be
effective in neurodegeneration (like in cardiovascular
diseases)
* More accurate diagnostics in early stages could be
used to enrol more accurately prodromal PD patients –
making drug trials cheaper and allow new drug
candidates higher effectiveness (treating early stage
instead of late stage)
Implicaiton of research for Theraputics
Early detection will enable earlier intervention
(stopping the disease before it gets into the brain)
* Neuronal aggregates in the ENS are modulated by
tissue resident macrophages – novel therapeutic
target in the periphery
* CNS neurodegeneration might be mediated by Tcells – immunosuppression could be used to slow
progression
