Extra information

Question 1

What diameter to the axons in the PNS and CNS have to be to be either myelinated or unmylinated?

Answer 1

PNS

<2 µm= unmyelinated

1-2 µm= myelinated

CNS

>0.2 µm myelinated

Question 2

What is de-differentiation of cells and how do schwann cells doing this help wallerian degeneration?

Answer 2

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

Question 3

How is Long-term potentiation (LTP) affected in AD?

Answer 3

• 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

Question 4

How does Abeta form plaques?

Answer 4

soluble monomer –> soluble oligomer –> Protofibrils –> fibrils –> plaques

Question 5

How does Abeta cause excitotoxicity?

Answer 5

Abeta –> PrPc binding to mGLUR5 –> Fyn –> NMDAR –> excitotoxicity

Question 6

Whats chromatolysis and why does it occur for axon regeneration?

Answer 6

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

Question 7

Whats the formula for calculating cerebral perfusion pressure and what is the ‘normal’ range of values for each?

Answer 7

Cerebral perfusion pressure= mean artieral pressure - intracranial pressure

CPP= 60-80 mmHg

MAP= 70-100 mmHg

ICP= 5-15 mmHg

Question 8

What are OECs attracting attention for?

Answer 8

Their potential use in neuronal repair (sun et al., 2019)

Question 9

What is the innate and adaptive immune response?

Answer 9

Innate: Physical, chemical and cellular defenses against pathogens

Adaptive: carried out by WBC

Question 10

Tell me about NO and ROS role in stroke?

Answer 10

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

Question 11

What are tight junctions?

Answer 11

Prevent leakage of solutes and water and seals between epithelial cells found in brain capillary cells

Question 12

What are A1 astrocytes induced by?

What does it cause?

What diseases is it found in?

Answer 12

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

Question 13

Tell me about ApoE4 and Abeta

Answer 13

ApoE4 binds to Abeta at residues 12-28 and leads to accumulation and disease progression

Question 14

Tell me about CSF1R, what its implicated in and therapeutics against it

Answer 14

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

Question 15

What does the ECM help with?

Answer 15

Helps cells bind together and regulates a number of cellular functions such as adhesion, migration, proliferation and differentiation

Question 16

What an experiment done which tried to use the PNS environment within the CNS for repair.

Tell me author and year

Answer 16

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

Question 17

What are the current limitations with stem cells with regeneration and repair?

Answer 17

• 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

Question 18

What plays a role in the development of secondary injuries that occur following TBI?

Answer 18

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

Question 19

Do homeostatic failures lead to any chronic ND?

Answer 19

Mitochondrial dysfunction with homeostatic failure leads to PD

Question 20

What things cleave the APP in AD?

Answer 20

BACE1= Beta-secretase

gamma-secretase= Presenilins (PS1 and PS2) are part of gamma-secretase complex

Question 21

Tell me the steps to the formation of the growth cone

Answer 21

1. influx of Ca2+
2. Membrane depolarisation
3. Activation of voltage-gated Ca2+ channels and release of Ca2+ from intracellular stores
4. Ca2+ activates calpains which digest spectrin cortex
5. Avtin and microtubules become depolarised
6. Vacuole internalisation
7. Membrane collapses at cut end
8. Membrane forms sealing patch at cut end
9. Ca2+ levels decrease to normal
10. Actin and microtubules are repolymerised
11. Actin filaments assemble to generate force at leading edge of lamellipodium
12. microtubules polymerise and point their +ve end towards the plasma membrane

Question 22

How do OECs help with regeneration?

Answer 22

• Provide trophic support
• Phagocytose debris
• allows cells and axons to integrate through glial scar rich regions

Question 23

How do hydrogels help with regeneration and repair?

Answer 23

• Mimic ECM
• Provide physical or topographical cues for axonal growth

Question 24

How does electrical stimulation help with regrowth and repair?

Answer 24

CPGs and locomotion

Question 25

What are the roles of normal Tau and then what happens when Tau is abnormal?

Answer 25

**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

Question 26

With stroke evolution, what is the pathway that occurs during the rapid response?

Answer 26

_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

Question 27

In the stroke evolution pathway, the secondary response is the malfunction of the ATP dependent process, explain this

Answer 27

Question 28

In the delayed response, inflammation and apoptosis occurs, what is the apoptotic pathway?

Answer 28

The major steps in apoptosis are as follows 1. Cell shrinks 2. Cell fragments 3. Cytoskeleton collapses 4. Nuclear envelope disassembles 5. Cells release apoptotic bodies Major apoptosis proteins * Killer proteins i.e., Caspases * Destruction proteins * Engulfment proteins

Question 29

How can the misfolded proteins in prion lead to synaptic degeneration?

Answer 29

**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

Question 30

What is excitotoxicity?

Answer 30

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

Question 31

The evidence of excitotoxicity as a mechanism of ND in stroke versus AD?

Answer 31

**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