Lecture 15: Astrocytes Continued Flashcards
list of the functions of astrocytes
formation of the blood brain barrier cerebral blood flow modulation of neural transmission myelinating activity of oligodendrocytes neuroprotection glial scar formation neural stem cell metabolism water transport synapses formation and function physical functioning of the Brian
Role of astrocytes during non-inflammatory conditions
non inflammatory state is also known as the steady state
Astrocytes interact with neurons, oligodendrocytes and also blood vessels in the form of these astrocytic end feet and they also interact with microglia as well, important in the tripartite synapse and metabolic support here and glutamate recycling and uptake,we also know that the astrocyte end feet line the cerebral vasculature and they are constituents of the blood brain barrier and they can limit the infiltration of pathogens and peripheral immune cells into the central immune system as well, further more astrocytes control water homeostasis and in the cns have these aquaporin-4 and other channel proteins that are involved in bidirectional fluid exchange over the blood brain barrier
Role of astrocytes during inflammatory conditions
astrocytes alter in inflammatory conditions
Astrocytes become reactive (change their morphology similar to microglia do) and change morphology and chemical expression in response to infection and also secrete a plethora of inflammatory mediators that regulates the function of myeloid cells, of lymphocytes, and also of other cells such as oligodendrocytes and neurons
not only do astrocytes affect microglia, inflammatory microglia can also affect astrocytes with the production of molecule such as interleukin 10 and TGF alpha which can actually induce protective functions in the astrocytes but alternatively microglia can also produce other mediators such as interleukin 1 beta or TNF alpha which actually induce more of a pathogenic astrocytic function - astrocytes are shown to have a dual role and be heterogeneous and they can respond to the environment that surrounds them as well
In addition, during inflammation, reactive astrocytes can modulate the trafficking of peripheral immune cells into the CNS, once these peripheral immune cells have invaded they are close to the astrocytic end feet and this can have a positive and a negative effect - can utilise these peripheral immune cells as a defence mechanism
Glial scar
The main cellular component of the glial scar is astrocytes and the glial scar formation is a reactive cellular process involving these astrocytes that occurs after injury to the central neefvous system, like other scarring this scar is formed to protect and to start the healing process of the nervous system, unfortunately in the context of neuro degeneration the formation of glial scars has not been shown to be beneficial but also have detrimental effects
healthy normal tissue = the territories of the astrocytes do not overlap here
moderate astrogliosis = territories still do not overlap with each other
severe astrogliosis = extensive overlap of the process of the severe reactive and scar forming astrocytes and it really forms a barrier to where the inflammation is occurring
Reactive astrocytes in the formation of glial scar steps
from resting astrocytes to reactive astrocytes there are a lot of changes - can become hypertrophic (get bigger), migrate, proliferate, change in gene expression
Many years it was believed that this severe astrogliosis and the formation of the glial scar inhibits axonal regrowth and that it is detrimental for neurological outcome but now there is an increasing amount of evidence that suggests that astrocytes also play a beneficial role in disease as well
resting astrocyte does hypertrophy - forms reactive astrocyte - then migration and proliferation ro form the glial scar
Astrocyte responses after CNS injury
In A what we have is resting astrocytes (in black) and they are contributing to the vascular support and blood flow regulation I.e. the steady state and are also contributing to the synaptic activity regulation and plasticity
Now in B, the injury results in the resting astrocytes to transform into the reactive astrocytes in orange and they contribute to the BBB permeabilisation and the subsequent leukocyte infiltration (infiltration of macrophages) which are important for actually going to the site of damaged tissue and mopping up debris as well as the astrocytes that can do this, also importantly the astrocytes are protecting the synapses as they begin to crowd around and protect the synapses
At C what we see is quite different, we see a lot of reactive astrocytes/ lots of proliferating astrocytes and they are limiting the cell spread of the macrophages, the astrocytes form a barrier around the macrophages and they can still pick up/phagocytosis debris in this area at the same time, astrocytes are starting to stabilise the blood brain Barrier as well
Finally at D what we are seeing is that the reactive astrocytes are contributing to the blood brain barrier repair and have formed a glial scar which is further limiting the inflammatory cell spread and stabilising the surrounding area to protect the surviving neurons, this part of the tissue is not going to be very functional but the neurons/synapses have been spared, so this shows how important this mechanism could be in protecting tissue and aiding the repair of tissue therefore these reactive astrocytes can have a beneficial effect in the tissue - the issue is that if there is too much reactive astrocyte present and therefore too much amyloid beta there then it causes a self fulfilling inflammatory state where astrocytes are inducing microglia and microglia are inducing reactive astrocytes and you have continuous inflammation occurIng and therefore you have cell death occurIng
Reactive Astrocyte-Mediated Neuroprotection
There is no CNS disease that does not substantially involve astrocytes
neuroprotective functions
debris clearance - phagocytosis of cell debris and neurotoxic factors
blood brain barrier - repairing leakiness to limit extravasation of blood components
glial scar - physical barrier to limit peripheral nerve cell infiltration
inflammation - secretion of anti-inflammatory factors &supression of pro-inflammatory signalling mechanisms (dependent what is happening in the tissue at the time)
Glutamate excitotoxicity - sequestering of excess glutamate
purpose of glial scar
glial scar - physical barrier to limit peripheral nerve cell infiltration
Astrocytes ensheath blood vessels up to
95%
Astrocytes and blood flow …
́ Astrocytes ensheath synaptic contacts
́
Astrocytic processes have glutamate receptors
Same astrocyte or astrocyte network - endfeet on blood vessel
́Trigger/stimulus
́Transient local increase in intracellular Ca2+
́Ca2+ propagated to astrocytic endfeet via endoplasmic reticulum
Endfeet at BVs – high connexin (Cx) expression
Astrocytes release vasoactive metabolites - and increase the blood from here and increased blood flow increases the importation of glucose and lactate from blood
Energy and astrocytes and getting it to other cells
Majority of energy comes from glucose directly in the blood to the neurons but the astrocytes and oligodendrocytes are also important contributors to energy in the neurons when the glucose levels are low and neuron activity is high
The brain’s blood vessels features
Different from the rest of the body
We know that these blood vessels create a barrier between the blood and the brain tissue and this is known as the blood brain barrier
Blood is a dynamic environment with variable levels of different substances such as hormones, glucose and potential pathogens in our blood so we need an environment on our brain that is very stable and protective and this is what the blood brain barrier is important for
The discovery of the blood brain barrier (BBB)
Paul Ehrlich injected blue dye into the bloodstream of a mouse and the dye infiltrated all tissues except the brain and spinal cord
dye showed there was a blood brain barrier
also when the dye was injected into the brain it did not travel to any other part of the body (no other organs became blue, only the brain)
_____ junctions important in maintain the BBB
tight
Is the BBB selective?
yes, selected components allowed in, lots of types of diffusion to get stuff in but it is very controlled
drugs are hard to get in so have to use different mechanisms
Maintenance of homeostasis and the blood brain barrier
BBB is needed for the maintenance of homeostasis
Lots of neural signalling in the CNS and this relies orecisely in ions moving across the cell membrane so we can generate the electrical signals at synapses and for axonal conduction, need to make sure that there is a tight balance of neurotransmitter (glutamate) release and recycling therefore maintaining a very stable homeostatic environment is important
BBB provides a selective advantage given by the fine control of the brains ionic environment
Invertebrates BBB is actually gale*/glial based but through evolution the barrier function shifted to the endothelium which is specialised to the exchange of blood to the brain whereas the glial cells are more for controlling the local ionic environment CHECK THIS GALE CELL THING IM CONFUSED is it meant to be glial?
Protection and the BBB
BBB functions as a protective barrier, shields that part of the CNS from neurotoxic substances
important to have it because we know for example that if bacteria gets through the BBB we can get bacterial meningitis
Blood vessels and the BBB
Blood vessels made of endothelial cells and the spaces between them in the brain is much tighter compared to the rest of the body, only particular molecules can get through these endothelial cell gaps such as oxygen, water, caffeine, alcohol,it is a very tightly regulated barrier
BBB structure
blood vessel lined with astrocytes end feet and pericytes
pericytes have smooth muscle properties, reside right beside the capillaries as well
endothelial cells (blood vessel cells) are forming the tight junctions
Basement membrane - layers of complex extracellular matrix proteins and they provide support for the endothelial cells, separating them from the underlying tissue as well
BBB allows …
small gases such as N2, O2, and Xe. permeable to molecules with mass <400 Da and fewer than 10 hydrogen bonds;
small lipophilic molecules
Glucose
fatty acids
Amino acids
Some micronutrients
