MM-Essential neuroscience Part B

Question 1

Astrocytes

Answer 1

-starshaped
-Highly Branched
- Non-Overlapping domains

Question 2

Composition of Astrocyte network

Answer 2

Glial Syncytium-Gap Junctions- movement of water and ions (small molecules) between Astrocytes

Question 3

The role of the Tripartite synapse

Answer 3

Astrocyte membrane receptors allow monitoring and support of the pre and Post synaptic junction.

Glutamate transporters are expressed on the astrocyte membrane:

-removal of excessive neurotransmitter Glutamate.
(maintain efficient transmission and prevent desensitisation of post-synapse)

-recycling of glutamate to glutamine, which is then secreted from the astrocyte for uptake and reuse

Question 4

Astrocytes act as a network for Potassium Spatial Buffering

Answer 4

Astrocyte membrane is hyper-polarised but not excitable (-80mV)

Potassium channels are abundant on the astrocyte membrane and allow inward flow of K+

K+ taken up from areas of high concentration can be shared across the network along chemical
gradients.

Question 5

Calcium signalling in the astrocyte network

Answer 5

Astrocyte not electrically excitable-can use Ca2+ to synchronise activity.

stimulation with glutamate- Internal Ca2+ oscillation.

release of Ca2+ stores linked to release of Gliotransmitters.

Question 6

Gliotransmitters

Answer 6

Glutamate
ATP
D-serine
TNF alpha

Question 7

Neurovascular coupling

Answer 7

Higher neuron activity requires increased blood flow.

Activation of metabotropic (long lasting) glutamate receptors (mGluR) -intracellular Ca2+ stores released:

1-Production of vasodilation inducing cyclooxygenase (COX)

2-Opening of ‘big potassium channels’ (BK), increasing
extracellular K+ concentration -vasodilation

Question 8

Blood-Brain Barrier maintenance

Answer 8

-Trophic support:
Glucose
Hormones
Lipids
Amino acid

-removal of waste products

Question 9

main form of energy production in the brain.

Answer 9

Oxidative phosphorylation

-Metabolic flexibility allows neurons to switch to glycolysis under
anaerobic conditions

(however neurons do hold a large store of glucose/glycogen)

Question 10

Pyruvate-Lactate Shuffle

Answer 10

1.Astrocytes transport glucose
from the vasculature (bv).

2.Astrocytes can store glucose by
converting to glycogen.

3.Glucose is converted to pyruvate for astrocyte metabolism.

4. Astrocytes convert pyruvate to lactate by Lactate dehydrogenase.

5.Lactate is release for uptake by neurons via monocarboxylate transporters.

6.Lactate is converted to pyruvate by lactate dehydrogenase for neuron oxphos metabolism.

Question 11

summary of Astrocytes in brain health and function

Answer 11

• Regulating blood flow and supply of oxygen (Neurovascular unit)
• Clear excessive neurotransmitter from synaptic cleft
• Regulate ion homeostasis
• Signal to neurons and glia by release of ‘gliotransmitters’
• Provide metabolic support to neurons

Question 12

role of Microglia

Answer 12

• is a Macrophage
• ## surveillance and monitoring of brain health.

Question 13

Neuroinflammation

Answer 13

a mixed cellular response to brain
infection or damage involving innate and adaptive responses of
resident brain cells and circulating immune cells

Question 14

The 2 stages of Microglia activity

Answer 14

1. Homeostatic -Rumified Shape
2. Reactive

Question 15

In its Active form Microglia…

Answer 15

secrete inflammatory Cytokines - activating other glial cell activity

Question 16

microglial Phagocytosis

Answer 16

• Phagocytose Invading pathogens
  -refine neural circuits by pruning ‘weak’ synapses

Question 17

Pruning of weak synapses

Answer 17

-Weak synapses are labelled by C1q and C3, compliment factors.

-microglia detect compliment factors on the synapse using C3 receptors

-engulf material

Question 18

Neurodegenerative Disease

Answer 18

-progressive neurological diseases where neurons loose function and die

two sub-classes:
-Movement Disorders
-Dementia

Question 19

Dementia

Answer 19

-Family of diseases associated impairment of cognitive function
-age associated loss of memory,
reasoning, judgement and executive function.

Alzheimer’s disease
Vascular dementia
Frontotemporal dementia Sclerosis
Dementia with Lewy Bodies

Question 20

Alzheimer’s disease

Answer 20

Cognitive Symptoms: Primary symptoms of AD are a loss of memory and cognitive function

Psychiatric symptoms: Delusions, hallucinations, depressed mood, and agitation (including violent outbursts)

Physiological Problems: disrupted sleep, incontinence, and difficulty swallowing are seen.communication skills are diminished, social withdrawal, loss of language

Question 21

Vascular dementia

Answer 21

Small vessel disease associated with ‘mini-strokes’, variable cognitive dysfunction

Question 22

Frontotemporal dementia

Answer 22

Behaviour, mood, personality.
Related to Amyotrophic Lateral Sclerosis

Question 23

Dementia with Lewy Bodies

Answer 23

Cognition, visual perception, sleep
disruption. Related to Parkinson’s Disease

Question 24

therapeutics for Alzheimer’s disease

Answer 24

Memantine:
-NMDA glutamate receptor antagonist Preferentially block overactive NMDA glutamate receptors

Rivastigmine, Galantamine, Donepezil:
-Acetyl-cholinesterase inhibitors Block breakdown of acetyl-choline in the synaptic cleft

Question 25

Alzheimer’s Disease leads to pronounced degeneration of which parts of the ageing brain

Answer 25

- Cerebral Cortex: higher level processing, memory, reasoning, language, thought, emotion - Hippocampus: encoding short term memory, consolidating long term memory - Entorhinal Cortex: network point allowing information to enter and leave the hippocampus

Question 26

what two abnormal deposits are found in an Alzheimer's brain ?

Answer 26

- Neurofibrillary Tangles - Amyloid Plaques / senile Plaques

Question 27

Amyloid Plaques / senile Plaques

Answer 27

-Large extracellular protein accumulations primarily composed of amyloid beta (Aβ42)– a 42 amino acid fragment of the Amyloid Precursor Protein (APP)

Question 28

Neurofibrillary Tangles

Answer 28

-fibrous intracellular inclusions in neuron cytoplasm. -Composed of hyperphosphorylated tau protein (noromally associated with cytoskeleton microtubules) Pyramidal neurons are particularly susceptible to NFT formation

Question 29

Spread of Amyloid Plaque and Neurofibrillary Tangle Pathology during AD progression

Answer 29

Neurofibrillary Tangles: Detected in entorhinal cortex during early stages of AD - Spread to Cortex and Hippocampus during disease progression Amyloid Plaques: First occur in cerebral cortex - Spread to hippocampus and distribute widely throughout AD progression

Question 30

Role of non-nueronal cells in AD Pathology

Answer 30

Microglia: Become reactive- direct contact with amyloid plaques reactivate pruning, removing adult synapses Astrocytes: -Reactive astrocytes release pro-inflammatory cytokines -Downregulate glymphatic clearance activity Vasculature: -Breakdown of blood brain barrier -allowing normally restricted molecules systemic circulation to enter the brain i.e. inflammatory factors, peripheral immune cells

Answer 31

Mutations in APP and gamma secretase enzymes are associated with early onset Alzheimer’s disease

Question 32

Motor Neuron Diseases

Answer 32

Family of diseases associated with death of motor neurons - loss of motor neurons from cortex, brainstem and spinal cord Primary Motor Cortex

Question 33

Amyotrophic lateral sclerosis (ALS)

Answer 33

- Muscle stiffness, fasciculations, weakness loss of neuromuscular junction connections SOD1(Superoxide Dismutase 1 ) -over expression results in loss of motor function. TDP43- splcing of s (No Muscle Nourishment Lateral Scarring)

Question 34

Gene Therapy for ALS

Answer 34

Tofersen: -Antisense oligonucleotide (ASO) drug -blocks production of SOD1, reducing production of aggregating protein -uses synthetic single stranded RNA to disrupt gene expression