Extra information Flashcards
What diameter to the axons in the PNS and CNS have to be to be either myelinated or unmylinated?
PNS
<2 µm= unmyelinated
1-2 µm= myelinated
CNS
>0.2 µm myelinated
What is de-differentiation of cells and how do schwann cells doing this help wallerian degeneration?
De-differentiation
- when a differentiation cell retrogresses to its initial form
- Halts expressed of myelin-related genes
- Re-expresses many immature schwann cell markers
wallerian degeneration
- de-differentiation in wallerian degeneration following nerve injury helps to promote nerve repair and functional recovery
How is Long-term potentiation (LTP) affected in AD?
- Amyloid beta decreases the LTP of hippocampal circuits
- ABO blocks LTP, a synaptic correlate to learning and memory
- Soluble Aβ Oligomers Inhibit Long-Term Potentiation through a Mechanism Involving Excessive Activation of Extrasynaptic NR2B-Containing NMDA Receptors
- This was examined using filed EPSPs and whole-cell recordings in Wt mice hippocampal slices
Li et al., 2011
How does Abeta form plaques?
soluble monomer –> soluble oligomer –> Protofibrils –> fibrils –> plaques
How does Abeta cause excitotoxicity?
Abeta –> PrPc binding to mGLUR5 –> Fyn –> NMDAR –> excitotoxicity
Whats chromatolysis and why does it occur for axon regeneration?
Chromatolysis is a reactive change that occurs in the cell body of damaged neurons
It involveds the dispersal and redistribution of Nissl substances (rough ER and polyribosomes)
This occurs to meet an increased demand for protein synthesis for axon regeneration
Whats the formula for calculating cerebral perfusion pressure and what is the ‘normal’ range of values for each?
Cerebral perfusion pressure= mean artieral pressure - intracranial pressure
CPP= 60-80 mmHg
MAP= 70-100 mmHg
ICP= 5-15 mmHg
What are OECs attracting attention for?
Their potential use in neuronal repair (sun et al., 2019)
What is the innate and adaptive immune response?
Innate: Physical, chemical and cellular defenses against pathogens
Adaptive: carried out by WBC
Tell me about NO and ROS role in stroke?
NO
- beneficial for lowering blood pressure
- promotes reperfusion and cytoprotection
- But if levels get too high it can be toxic for the brain tissue
ROS
- Implicated in brain injury after ischemic stroke
- Overwhelms antioxidant defence and causes further tissue damage
What are tight junctions?
Prevent leakage of solutes and water and seals between epithelial cells found in brain capillary cells
What are A1 astrocytes induced by?
What does it cause?
What diseases is it found in?
induced by…
- activated microglia which are active due to CNS injury and disease (reactive astrocytes)
- Microglia secrete –> Il-1alpha, TNF and C1Q –> A1 astrocytes
- A1 astrocytes induce the cell death of neurons and oligodendrocytes
- A1 found in AD, HD, PD and MS
Liddelow et al., 2017
Tell me about ApoE4 and Abeta
ApoE4 binds to Abeta at residues 12-28 and leads to accumulation and disease progression
Tell me about CSF1R, what its implicated in and therapeutics against it
CSF1R (colony stimulating factor 1 receptor)
- Tyrosine kinase transmembrane receptor
- Modulates microglial homeostasis (proliferation and activation), neurogenesis and neuronal survival in CNS
- LOF mutations –> AD
JNJ-527 is a CSF1R inhibitor to help treat AD
GW2580 is an antagonist of CSF1R
What does the ECM help with?
Helps cells bind together and regulates a number of cellular functions such as adhesion, migration, proliferation and differentiation
What an experiment done which tried to use the PNS environment within the CNS for repair.
Tell me author and year
David and Aguayo (1981)
Performed an experiment on rat
Inserted a graft
The aim was that the cell transplant would create a bridge over the scar and produce a permissive substrate and promote remylination
However, it resulted in the axons growing into the graft but not beyond into the CNS again
What are the current limitations with stem cells with regeneration and repair?
- Robust lineage with specific deifferentiation of stem cells with desired functional attributes
- Deciding whats best i.e., using precuroses of completely undifferentiated
- Understanding role of host tissue
What plays a role in the development of secondary injuries that occur following TBI?
Glutamate excitotoxicity plays a role in the development of secondary injuries that occur following TBI, and contributes to the expansion of total volume of injury
Do homeostatic failures lead to any chronic ND?
Mitochondrial dysfunction with homeostatic failure leads to PD
What things cleave the APP in AD?
BACE1= Beta-secretase
gamma-secretase= Presenilins (PS1 and PS2) are part of gamma-secretase complex
Tell me the steps to the formation of the growth cone
- influx of Ca2+
- Membrane depolarisation
- Activation of voltage-gated Ca2+ channels and release of Ca2+ from intracellular stores
- Ca2+ activates calpains which digest spectrin cortex
- Avtin and microtubules become depolarised
- Vacuole internalisation
- Membrane collapses at cut end
- Membrane forms sealing patch at cut end
- Ca2+ levels decrease to normal
- Actin and microtubules are repolymerised
- Actin filaments assemble to generate force at leading edge of lamellipodium
- microtubules polymerise and point their +ve end towards the plasma membrane
How do OECs help with regeneration?
- Provide trophic support
- Phagocytose debris
- allows cells and axons to integrate through glial scar rich regions
How do hydrogels help with regeneration and repair?
- Mimic ECM
- Provide physical or topographical cues for axonal growth
How does electrical stimulation help with regrowth and repair?
CPGs and locomotion
What are the roles of normal Tau and then what happens when Tau is abnormal?
Normal Tau
- A Microtubule-associated protein
- Promotes microtubule self-assembly by tubulin and stabilises those already formed
Abnormal Tau
- Reduced binding to microtubules
- MT tracks collapse
- Compromised axonal transport
- Disruption of synaptic connectivity
With stroke evolution, what is the pathway that occurs during the rapid response?
Normal aerobic mechanism
Oxygen Glucose
Mitochondria respiration
Cellular ATP
Ongoing consumption
The stage of mitochondrial respiration is affected in stoke and leads to…
- deletion of cellular ATP
- ROS
- Excessive ATP usage
- Intracellular acidification
- Malfunction and cell death
In the stroke evolution pathway, the secondary response is the malfunction of the ATP dependent process, explain this
In the delayed response, inflammation and apoptosis occurs, what is the apoptotic pathway?
The major steps in apoptosis are as follows
- Cell shrinks
- Cell fragments
- Cytoskeleton collapses
- Nuclear envelope disassembles
- Cells release apoptotic bodies
Major apoptosis proteins
- Killer proteins i.e., Caspases
- Destruction proteins
- Engulfment proteins
How can the misfolded proteins in prion lead to synaptic degeneration?
Cellular prion protein (PrP^c) is a high affinity binding site for ABO
then link to…
- ABO in alzheimers and effect on synapse plasticity, dendritic spin loss and LTP (Nr2B and NMDAR and excitotoxicity)
- draw fig of APP –> plaques
- link to oxidative stress, UPS, aggregation of misfolded proteins etc.
- AB to ApoE4 –> microglia activation
- A1 astrocytes
- Gomez-nicola et al. 2019
What is excitotoxicity?
Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death
The evidence of excitotoxicity as a mechanism of ND in stroke versus AD?
Stroke
- evolution of stroke
AD
- ABO link to LTP in hippocampus
- increases activation of extracellular NR2B containing NMDAR
- excitatory glutamate at NMDAR is critical for synaptic plasticity and survival of neurons.
Excess NMDAR activity promotes cell deathm underlying a potential mechanism of ND occuring in AD
