Lecture #9 Flashcards
what are the two main pathogenic hypothesis for the induction of neurodegeneration?
the amyloid cascade hypothesis and the Tau hyperphsophorylation hypothesis
describe the amyloid cascade hypothesis:
it has been demonstrated in animal models and brain tissues from patents that there can be the accumulation of extracellular β amyloid (βA) that forms tangles, derived by not regulating proteolytic cleave of amyloid precursor protein
accumulation is toxic to neurons affecting their survival
describe the tau hyperphosphorylation cascade:
Tau is a protein usually acclimated in the axonal shaft, they hyperphosphorylation induces the aggregation of the protein and tis tau deposit inside the cells affects Thea axonal transport and therefore induces neuronal death
what is the most famous transgenic mouse model to study AD?
5XFAD → APP and PSEN1 are added to genome 5
what are microglia associated with neurodegeneration called?
disease associated microglia (DAMs)
are DAMs protective or detrimental for the CNS?
literature is very contradictory:
papers support the idea that microglia help the CNS maintain homeostasis (KO models with Trem2)
other papers say that DAMs and Trem2 are detrimental for the homeostasis of the CNS
describe the formation of the CNS in development:
neurons and microglia are derived from neuroepithelium soon after the closure of the neural tube and the thickening of the neuroepithelial radial glial layer
later on we have the generation of the germinal niche, the ventricular zone and from asymmetric cell division of radial glia of neuroepithelial cells we have the generation of all the neurons in the CNS
describe the process of astroglial genesis in rodents:
intermediate progenitors of astrocytes are derived from an assymmetric cell division of the neuroepithelial cells, usually they lose their apical connection with the membrane, then they retract the basal connection and they migrate from the germinal niche to the cortical plate were they start to differentiate into astrocyte progenitors
what is one way that astrocytes are similar to microglia?
they are self-sustaining: some astrocytes can proliferated during the normal post-natal life and replace dying cells
what are the two subdivisions of astrocytes?
star-shaped astrocytes and elongated astrocytes
name the two different types of star-shaped astrocyte:
- protoplasmic astrocytes: typically accumulating in gray matter in the cortical plate where we have neurons
- fibrous astrocytes: in the white matter
where are both types of elongated astrocytes found?
muller cells in the retina and Bergmann glia in the cerebellum
what happens after the elongation of the axonal shaft?
formation of myelin that is fundamental for the saltatory conduction of the impulses
which portions of the CNS makes up the white and grey matter?
myelin is white while in the regions where we have the cell body of neurons the color is grey
what is the territory of an astrocyte called?
domain - a region where there is the cell body and a cytoplasmic arborization
what is used to track astrocytes in the CNS?
GFAP (glial fibrillary acid protein) → is not an absolute marker of astrocyte because it is usually expressed by specific subsets of astrocytes or in general by reactive astrocytes
normal antibody and immunohistochemistry are used or S100β
describe the ratio of astrocytes to neurons in humans, rodents, and worms:
worms: 6:1
rodents: 3:1
humans: 1:1
suggests that the role of astrocytes increases in importance with the sophistication of the CNS
describe the connection difference in astrocytes between mice and humans:
a single protoplasmic astrocyte in rodents can connect to around 48 cytoplasmic bundles and can cover up to 20,000 synapses
in humans a single astrocyte can cover 2 million synapses
during development, what are astrocytes essential for developing?
the BBB
what is the membrane potential for neurons?
-90 mV
what is the rule the governs the voltage and current in astrocytes?
Ohm’s rule: V=RI
what is the rule the governs the voltage and current in astrocytes?
Ohm’s rule: V=RI
what is the rule the governs the voltage and current in astrocytes?
Ohm’s rule: V=RI
what is the rule the governs the voltage and current in astrocytes?
Ohm’s rule: V=RI
what is the rule the governs the voltage and current in astrocytes?
Ohm’s rule: V=RI
why are astrocytes considered Ohmic cells?
they don’t have voltage gated channels opening at specific cell membrane potentials → they respond to the variation of cell membrane with the simple Ohm rule
they are not involved in the synaptic / electrochemical transmission of signals
describe the IV curve in neurons vs astrocytes:
a line in astrocytes, and a curve in neurons
what are astrocytes connected by, and what does this allow for?
gap junctions → allows for the diffusion of small molecules important for spreading information from one astrocyte to another
how are astrocytes similar to microglia in terms of spatial orientation?
they never overlap
how do astrocytes enter into contact with vessels?
cytoplasmic hands and feet, that is fundamental for the blood brain barrier → enter in contact with each other through gap junctions that are at the end of the cytoplasmic bundle, but in physiological conditions they never overlap
what are the 5 key functions of astrocytes?
- regulate the molecular homeostasis of molecules and ions
- regulate the pH of the extracellular space and the concentration of glucose
- regulate neurogenesis
- regulate the water content in the brain and the BBB
- regulation of neurotransmitters in the cleft
describe the tripartite synapse:
astrocytes collaborate with the system wrapping the individual synapses
make up of the presynaptic terminal, the postsynaptic terminal, and the wrapping astrocytes
what are astrocytes able to release into the extracellular space?
a small amount of soluble signal → TNF-⍺ (classical Proinflammatory cytokine involved in the inflammation of neurons) in front of neurons in order to regulate the distribution and total amount of glutamate receptor in the postsynaptic terminal
how are astrocytes involved in synaptic communication?
they are able to quickly remove the neurotransmitter released by the presynaptic terminal in the cleft to avoid new stimulation
what other function do astrocytes perform besides wrapping the synapses?
they also seal the synapses → preventing the neurotransmitter in the cleft from exiting by simple diffusion and entering the extracellular space where there is another synapse
what can happen if potassium accumulates outside the cell?
too much potassium can reduce the membrane potential of neurons, reducing the distance between the resting membrane potential and the critical threshold, meaning that a subtle stimulus from a synapse could be enough to fire the neuron
how do astrocytes help to remove excess potassium?
use specific side channels that require energy to operate and in a very efficient way the potassium that is accumulating here can be removed
what do astrocytes need to function?
ATP
what neurotransmitter is used by man synapses, and what happens if there is too much?
glutamate - we don’t want the spillover of glutamate because it can activate other synapses we do not want to be activated → excitotoxicity
astrocytes sealing the synapses to prevent the contamination by non-synaptically related glutamate allows for the faster removal of glutamate from the cleft causing a rapid replenishment of glutamate in neurons
in what case is glutamate not toxic in excess?
if we have an enzyme that transforms glutamate into glutamine
describe the glutamate - glutamine shuttle:
astrocytes can capture glutamate, transform it into something nontoxic (glutamine) release this molecule into the extracellular space allowing the neurons to capture the glutamine, transform it back to glutamate that is available for a second round of transmission
how do astrocytes make energy with glucose?
the can capture glucose in the circulation and through glycolysis convert it into pyruvate and lactic acid
how do astrocytes release the lactic acid created?
through the transporter MCT-2 into the extracellular space
MCT-1 is also expressed which allows lactate to cross from the extracellular space inside to the presynaptic terminal and use the Krebbs cycle to convert lactate into ATP
how can glucose be captured by neurons?
GLUT1 and GLUT3
describe the lactate shuttle and glucose homeostasis:
increased neuronal activity means increased energy requirement → a huge amount of glutamate is released and astrocytes start to capture it and convert it to glutamate
they need to acquire a huge amount of glucose and therefore they need to produce a huge amount of lactate → lactate is moving from astrocytes to neurons and therefore we have a perfect cycle
what is the “plan B” for astrocytes when glucose is not available?
astrocytes can provide glycogen from its own energetic reserve
what are the function of BMECs? (brain microvessle endothelial cells)
connected by tight junctions and help avoid the spillover of molecules from the blood circulation
what cells are around the BMECs, and what is their function?
pericytes - play an important role in the regulation of the BBB homeostasis, integrity, macrophage activity, and modulate blood flow
what are the function of perivascular macrophages?
like microglia - important in inflammatory disorders because they seem be the first type of activation of neuron in disorders
how is BMEC metabolism important?
they can destroy toxic molecules and prevent molecules from moving across the blood, as well as important to keep neurons functionally separate from the rest of the body
how do astrocytes regulate blood circulation?
they can induce vasodilation and vasoconstriction
how is vasodilation induced?
when glutamate enters the neuron, we also have the accumulation of calcium in the region outside of the presynaptic terminal (too much calcium = over activation of the system)
in response to the calcium arachidonic acid is related and can be converted into prostaglandins by Cox-1, inducing vasodilation
how is vasoconstriction induced?
under the same conditions as before, arachidonic acid can be converted into 2-HETE which is hydroxyeicosatetraenois acid, which interacts with P450 of BMEC which induces vasodilation
what types of channels do astrocytes express on their hands and feet, and which is the most famous?
aquaporin channels - aquaporin 4
what do the acquaporinis allow the astrocytes to do?
absorb water in order to shape the size of the extracellular space to modulate the size of the synapse
describe the activation of astrocytes:
they can be activated along a gradient
what is the first and easiest thing to look for in astrocyte activation?
GFAP expression
when we go into regions not far from the tissue damage, these cells up regulate GFAP and start to become hypertrophic → by measuring the size of the astrocytes we can see that the cell bodies start to increase
as astrocytes become hypertrophic, what do they form?
they start to proliferate and overlap producing a glial scar
how is the glial scar detrimental?
there is no space to repair or restore neuronal functionality
what is the goal of the glial scar?
to confine the damage
what is the classical marker of astrocytes that have gone into senescence?
β-GAL like activity → neurons and microglia can sense this factors and therefore astrocytes can contribute to a general inflammatory condition of the aging brain
