Neurodegenerative Diseases

Question 1

Define neurodegeneration?

Answer 1

Progressive loss of neurons

Question 2

Define neurodegenerative disease?

Answer 2

Disease caused by neurodegeneration

Question 3

When does neurodegeration start?

Answer 3

Any stage of life but most common ones are associated with ageing, rare ones start in childhood/from birth.

Question 4

What is the cause of earlier onset of neurodegenarative disease?

Answer 4

greater genetic contribution - likely monogenic mutation

Question 5

What is the cause of later onset of neurodegenarative disease?

Answer 5

sporadic / idiopathic disease

Question 6

Give an example of a nuerodegenerative disease from birth?

Answer 6

Spinal muscular atrophy (SMA)

Question 7

What parts of the nervous system do neurodegenerative diseases affect?

Answer 7

CNS/PNS sometimes both

Question 8

Are neurodegenerative diseases similair to each other?

Answer 8

no they are highly HETEROGENEOUS (vary alot)

in cases they are INHERENTLY PLEIOTROPIC, in other cases conditions may overlap phenotypes but have very diff genetic causes (diff mutations for one disease)

Question 9

Define pleiotropic?

Answer 9

Symptoms manifest differently in different people

Question 10

What is the common pattern (order) in neurodegenerative disease?

Answer 10

1) Molecular impairment in cell
2) decreased transmission at synapse
3) dying back of neurites (axons/dendrites)
4) cell death

Question 11

What is a neuron’s achilles heel?

Answer 11

Distance between axon terminal and nucleus (longer axons = longer transport = more dangerous)

Question 12

What is the myelin sheath made of in CNS vs PNS?

Answer 12

CNS - oligodendrocytes

PNS - schwann cells

Question 13

What are common features seen in neurodegenerative disease (from molecular level)?

Answer 13

protein aggregation (proteinopathies)
Lysosomal dysfunction (resulting in degredation)
Mitochondrial dysfunction
Associated inflammation via activation of glia

Question 14

Why is neurodegenerative disease incurable?

Answer 14

Signs don’t show until long after neurodegeneration started so early treatment not possible without early diagnosis. After diagnosis, too much damage already done

If CNS affected, hard to study affected tissue - can not identify problem until after death in brain pathology

Question 15

What is the most common neurodegenerative disease?

Answer 15

dementia

Question 16

What is the causal/correlation relationship of age with dementia?

Answer 16

onset of dementia usually in higher age, but dementia not normal part of ageing!

Question 17

What is dementia?

Answer 17

Fast and sudden decline in memory and other cognitive functions that impair quality of life - distinct from normal ageing symptoms

Question 18

What cognitive lapse happens in normal ageing?

Answer 18

GRADUAL decline in normal cognition and gradual changes in personality

Question 19

What are the 3 pathological hallmarks of dementia?

Answer 19

Brain shrinkage (+enlarged ventricles) causing lack of ability to form memories
Proteinopathies

Question 20

What are the 2 types of proteinopathies in dementia?

Answer 20

Amyloid plaques and neurofibrillary tangles

Question 21

What are amyloid plaues?

Answer 21

EXTRACELLULAR protein aggregates

enriched in alpha beta peptides

Question 22

What are neurofibrillary tangles?

Answer 22

INTRACELLULAR protein aggregates

- enriched in Tau protein

Question 23

What is another name for neurofibrillary tangles?

Answer 23

paired helical filaments

Question 24

How are amyloid plaques formed step by step?

Answer 24

AB fragment on a transmembrane protein called amyloid beta precursor protein (APP)
Beta secretase cleaves a peptide from transmembrane protein exposing AB peptide
gamma secretase cleaves AB peptide released it intro extracellular space when it accumulates forming extracellular amyloid plaque (proteinopathy)

Question 25

What are the pathological hallmarks of AD?

Answer 25

proteinopathies

Question 26

What is the amyloid hypothesis?

Answer 26

Mutations to 3 proteins involved in AB peptide process cause rare early onset of ALZHEIMERS - amyloid plaque cause of alzheimer’s disease

Question 27

What are the 3 proteins that are mutated in the formation of amyloid plaques in alzheimer’s disease?

Answer 27

APP (transmembrane protein itself)

PSEN1 and PSEN2 (presenilin-1 and presenilin-2 both a component of gamma secretase)

Question 28

What does Tau normally do?

Answer 28

Binds to microtubules on axons

Question 29

What happens to Tau pathologically?

Answer 29

Tau becomes hyperphosphorylated causing it to become displaced which goes onto aggregate forming tangles + also destabilises microtubules.

Question 30

What are the roles of microtubules in post-mitotic cells?

Answer 30

Structure/shape of cell
Positioning of organelles
Motorway for transporting vesicularcargo

Question 31

How does the loss of microtubules due to Tau aggregation (neurofibrillary tangles) cause in Alzheimers?

Answer 31

No more microtubules = no more motorway for transporting vesicular cargo = problem on longer axons - links back to achilles heel

Question 32

What is the Tau hypothesis?

Answer 32

Seen before amyloid plaques (suggests they come first) suggesting Tau is upstream of AB

Tau increases from early through to late stages - correlates cell death with progression of alzheimers

Question 33

When do neurofibrillary tangles form in AD?

Answer 33

Late onset so not genetic cause

Question 34

Does amyloid hypothesis or tau hypothesis cause alzheimers disease?

Answer 34

More evidence for amyloid but may not be a cause (inhibitting AB aggregation shows not difference)

Question 35

Which form of AB and tau is more pathogenic?

Answer 35

Oligomeric forms

Question 36

What are risk factors of AD (alzheimers disease?

Answer 36

Down syndrome (APP gene is on chromosome 21)
Gender (more in women)
High BP, cardiovascular disease, diabetes
Low education (low cognitive reserve)
head injury (trauma)
smoking and drinking
ONLY SMALL GENETIC RISK CONTRIBUTION FOR LATE ONSET AD

Question 37

What are the motor symptoms of parkinson’s disease?

Answer 37

1) resting tremor
2) bradykinesia (slow movement)
3) rigidity
4) postural instability (fall over)

Question 38

What are the non motor symptoms of PD?

Answer 38

Depression and anxiety
Loss of smell
Sleep disorders
Constipation

Dementia
Other psychiatric conditions

Question 39

What are the pathological hallmarks of PD?

Answer 39

LOSS OF DOPAMINERGIC NEURONS OF SUBSTANTIA NIAGRA

proteinopathy - lewy bodies

Question 40

What is the substantia niagra? and how does it look in PD?

Answer 40

Part of basal ganglia in midbrain - usually dark due to dopaminergic neurons - lost in PD = lack of pigmentation (normally should be dark)

Question 41

Which parts of the brain does PD affect?

Answer 41

Not only substantia niagra - dopaminergic neurones lost in other regions too

Question 42

What are lewy bodies?

Answer 42

INTRACELLULAR PROTEIN AGGREGATES

enriched in alpha synuclein protein (cyclical protein inside cell nucleus)

Question 43

What effect does Lewy bodies have on PD?

Answer 43

Not pathogenic unlike amyloid and tau in AD and dementia

Question 44

What are the 3 clear genetic causes of familial PD?

Answer 44

1) Early onset due to recessive mitochondrial conditions
2) Later onset (sporadic) due to automsomal dominant PD
3) mutations that cause PD-plus conditions