Autism Etiologies Flashcards
Evidence of neurodegeneration in autism
1) significantly decreasing amount of Purkinje cells in the brain
2) neuronal cell loss,
3) activated microglia and astrocytes,
4) proinflammatory cytokines,
5) oxidative stress,
6) elevated 8-oxo-guanosine levels
8-oxo-guanosine
one of the most common DNA lesions resulting from reactive oxygen species modifying guanine
Microglia
the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS).
Astrocytes
a sub-type of glial cells in the central nervous system - envelop synapses
Microglia
- the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS)
- maintain cerebral homeostasis
Describe the vicious cycle of oxidative stress
1) Oxidative stress causes damage to mtDNA
2) Damaged mtDNA leads to decrease in coding for proteins needed for electron transport chain
3) Decreased function of electron transport chain leads to decreased energy and increased free radicals (oxidative stress)
4) Increased oxidative stress causes damage to the cell membrane
5) Damage to the cell membrane leads to release of cytochrome C leading to apoptosis or cell death
6) Cell death leads to more oxidative stress
Describe microglial activation
- Rapid proliferation of microglial cells
- Migrate to site of infection
- M1 activated microglia: neurotoxic with release of pro-inflammatory cytokines
- Engulf dying cells, infectious agents, toxic proteins, and cell debris
List some pro-inflammatory cytokines
TNFalpha, IL-1B, IL-6, COX, Reactive oxygen species (ROS), Nitric oxide
M1 microglia
Responsible for inflammation
Functions of astrocytes
1) Induce formation of neuronal synapses
2) Formation and maintenance of BBB
3) Neurotransmission: component of tripartite synapse model
4) Homeostasis and turnover of glutamate
5) Metabolic regulation
6) Ion balance maintenance
7) Key role in development of the nervous system
Neuroinflammatory markers in ASCs
1) Microglial activation
2) Astrocytic activation with elevated levels of GFAP(glial fibrillary acidic protein)
3) Proinflammatory profile of cytokines in the brain, CSF and blood
4) Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation
Evidence of autoimmunity in autism
accumulation of T cells and astrocytes in postmortem brain tissue
brain blebs may be formed in response to the infiltration of T cells into the space between blood vessels and neural tissue, while the cell fragments they contain could come from the astrocytes that make up the glia limitans
Glia limitans
the final wall of defense separating neural tissue from foreign and toxic substances circulating in the blood
What is the BBB
The blood-brain barrier is a dynamic interface between the peripheral blood supply and the cerebral parenchyma, controlling the transport of material to and from the brain
BBB dysfunction in ASCs - specifics:
Perturbation of these processes:
Tight junctions between the endothelial cells of the cerebral microvasculature limit the passage of large, negatively charged molecules via paracellular diffusion.
Transcellular transportation across the endothelial cell is controlled by a number of mechanisms including transporter proteins, endocytosis, and diffusion.
BBB dysfunction in ASCs – basics
Increased permeability of the BBB leading to increased infiltration of peripheral material into the brain culminating in neuroinflammation and oxidative stress.
Microglial role in development
- help to set up the circuits of the brain by strengthening appropriate cell-to-cell connections and by eliminating improper connections in the brain
- regulate the plasticity of brain cells and prune synapses
Gliosis
proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes
Clostridia metabolites:
3-(3-hydroxyphenl)-3-hydroxypropionic acid (HPHPA) and 4-cresol
Clostridia metabolite effect
inactivate dopamine beta-hydroxylase, which is needed for the conversion of dopamine to norepinephrine
So what have heavy metals got to do with anything
Cause activation of microglial immune cytokines
What has glutamate got to do with anything
Causes activation of microglial cytokines
What determines severity of autism?
The stage at which the immune/excitotoxic stress caused by activation of microglial and the consequent release of cytokines, ROS and excitotoxins - brain dysfunction
An excess of extraneural glutamate
Can interfere with neuronal migration patterns, differentiation and synaptic development - abnormal brain architecture
Excitotoxicity
Activation of NMDA receptors by excessive glutamate
Brain cell death usually occurs
- impaired uptake if glutamate by glial transporters
* regulated by NF-κB
TNF-α induces
- IκB dégradation pathway
- triggers NF-κB nuclear translocation
- represses glial transporter
- elevates extracellular glutamate
- increases risk of glutamate toxicity
Dopamine dégradation causing neuro inflammation
Dopamine dégradation - ROS (toxic)
Dopamine cyclized o-quinone -> dopamine cyclized o-semiquinone -> NADPH depletion + o2 -> oxygen superoxide + dopamine-cyclized o-quinone
Dopamine dégénération
- O-quinone + cysteine residues on glutathione/proteins -> cisteinyl-dopamine conjugates
- > N-acetylcysteinyl dopamine thioether - apoptosis of dopamine cells
Stereotypy
norepinephrine deficiency
