Neurodegenerative Diseases Flashcards
1
Q
Define “Neurodegeneration”
A
Neuro (Relating to neurons) + Degeneration (Progressive loss)
2
Q
Define “Neurodegenerative disease”
A
Any disease caused by neurodegeneration
3
Q
Briefly describe neurodegenerative diseases
A
- Affects both CNS and PNS
- Begin at any stage of life
- The most common ones are associated with ageing
- Rarer types of neurodegenerative disease start in childhood or even birth
- Earlier age of onset = Greater genetic contribution
- Later age of onset = More likely a sporadic (or idiopathic) disease (unknown cause)
4
Q
Give some examples of neurodegenerative diseases
A
- Alzheimer’s disease: 65 years or older = CNS
- Parkinson’s disease: 40 years = CNS
- Huntingtons disease: 40 years = CNS
- Multiple Sclerosis: 20-50 years = CNS
- Motor neurone disease: 40-70 years = PNS
- Spinal muscular atrophy: From birth = PNS
5
Q
Are neurodegenerative diseases heterogenous or homogeneous?
A
Are highly heterogeneous
6
Q
In which 2 ways can Neurodegenerative diseases be seen as heterogenous?
A
- This can be due to:
- Some disease names are really umbrella terms: Conditions with overlapping phenotypes but distinct causes
- Some diseases are inherently pleiotropic: Symptoms can manifest differently in different people
7
Q
List some common features that some diseases have
A
- Many follow a similar pattern: There’s a standard way in which neurons are lost
1). Molecular impairment somewhere in the cell
2). Decreased transmission at synapse
3). “Dying back” of neurites (Axons and/or dendrites)
4). Cell death
Distance between axon terminal and nucleus = A neurons “Achilles heel”
8
Q
What is the term given to the distance between an axon terminal and nucleus?
A
- A neurons “Achilles heel”
- The weak point in any neuron because things have to be transported such a long way
9
Q
What else do neurodegenerative disease have in common?
A
- Frequently involve:
- Protein aggregation (proteinopathies)
- Lysosomal dysfunction
- Mitochondrial dysfunction
- Associated inflammation via activation of glia
10
Q
What is one limitation of a neurodegene disease?
A
- They rarely manifest overt signs and symptoms until long after the neurodegeneration has begun
- Early treatment is impossible without early diagnosis
- Therapeutic challenge is considerable
- For CNS disorders, studies of affected tissue is very difficult until death
- Advanced brain pathology is of little help to understanding the cause
- Neurodegenerative disease remain incurable
11
Q
Briefly describe Alzheimer’s disease
A
- The most common Neurodegenerative disease
- The most common cause of dementia
- Onset is usually > 65 years old but 10% are early onset starting at 30
- incidence rate: 10% of people aged 65+, 50% of people aged 85+
- Alzheimer’s disease is not a normal part of ageing, it’s a disease
12
Q
What is dementia?
A
- A decline in memory and other cognitive functions that impair your quality of life
- Impairments in dementia are distinct from “normal” cognitive lapses
13
Q
Give some situational examples of Alzheimer’s disease
A
- Getting lost in your own neighbourhood
- Not recognising a family member
- Strong & irrational changes in mood
- Sudden changes in personality
14
Q
How do we tell the difference between normal ageing and dementia?
A
- Normal ageing involves a gradual decline in normal cognition, gradual changes in personality
- Impairments in dementia are distinct from normal cognitive lapses
- Alzheimer’s disease is also fast and sudden
15
Q
Give a history of Alzheimer’s disease
A
- First described by Alois Alzheimer’s, a German psychiatrist and neuroanatomist in 1906
- Initial psychiatric and pathological observations in younger patients
- Discovered “Presenile dementia”
- Pathology then found to be widespread in older patients
16
Q
What is meant by the term “hallmark”?
A
- In general, in a piece of jewellery where you have the precious metal, they have stamps in it which tell you how much carrots the gold is and the office which recorded it
- In short, it’s the evidence that tell you what something is
17
Q
What are the pathological hallmarks of Alzheimer’s disease?
A
- Brain shrinkage: Quite clear
- Shrinkage of the hippocampus, Cerebral cortex and enlarged ventricles
18
Q
What are some other pathological hallmarks of Alzheimer’s disease?
A
- At the cellular level:
- Proteinopathies: The aggregation of proteins
- Has 2 types
- Amyloid plaques: Round bodies which sit outside the cell
- Neurofibrillary tangles: Sit within the cell
19
Q
Briefly describe the amyloid plaques
A
- Sit outside the cell
- Extracellular protein aggregates
- Enriched in Abeta peptides
20
Q
Briefly describe the Neurofibrillary tangles
A
- Sit inside the cell
- Also called paired helical filaments
- Intracellular protein aggregates
- Enriched in Tau protein
21
Q
What is the Abeta peptide?
A
- It’s a cleavage from a transmembrane domaine called the amyloid beta precursor protein (APP) by proteases
22
Q
What do these cleavages lead to?
A
- First there is a cleavage by B secretase -> another cleavage by Y secretase
- Which then accumulate and forms amyloid plaques outside the cell
23
Q
Describe the Amyloid hypothesis
A
- Mutations to 3 proteins involved in AB peptide processing are known to cause rare early onset forms of Alzheimer’s
- These proteins are known as
- APP, PSEN1 AND PSEN2
- Both Presenilin-1 and Presenilin-2 are components of Y secretase
Since early 1990’s “Amyloid hypothesis of AD” which states that Abeta and/or amyloid plaques are the causes of AD
24
Q
Describe Tau and Neurofibrillary tangles
A
- Tau normally binds microtubules in axons (are normally intracellular proteins)
- Hyperphosphorylated tau is displaced causing:
- Tangles
- Destabilised microtubules
25
Q
What is the importance of microtubules in neurites?
A
- In all post mitosis cells, microtubules have 3 main roles:
- Structure/Shape of the cell
- Positioning of organelles
- Motorways for transporting vesicular cargo
26
Q
Describe the Tau hypothesis
A
- In typical late onset Alzheimer’s disease (not genetic forms of AD)
- Seen before amyloid plaques
- Well correlated with cell death and progression
- Suggests Tau is upstream Abeta = Tau hypothesis
27
Q
So is the Tau hypothesis or the amyloid hypothesis correct?
A
- Still really controversial
- Probably more evidence for the amyloid but Therapies based on inhibiting Abeta aggregation so far haven’t worked
- Tangles and plaques may be red herringsAre they pathogenic or by standers? Or even protective? Oligometric forms of Abeta are more likely to be pathogenic
- Could both be downstream of other factors
28
Q
What are some other risk factors of Alzheimer’s disease?
A
- Down syndrome (APP is on chromosome 21)
- Gender (More common in women)
- High BP, Cardiovascular disease, diabetes
- Low education
- Head injury
- Smoking and drinking
- Only a small genetic risk contribution for late onset AD
29
Q
Describe Parkinson’s disease
A
- The second most common Neurodegenerative disease
- Onset usually 60-65 years of age, but 10% start before 45 years of age
- Lifetime risk: Males = 2% Females = 1.3%
- Like AD, Parkinson’s disease is incurable
30
Q
Give a brief history of Parkinson’s disease
A
- First reported in 1817 by James Parkinson, an east London physician
- Described it a “Shaking palsy”
- Identical symptoms described by a Hungarian physician, Ferenc Papai Pariz in 1690
- However, the similar observations stretch back to ancient Egypt
31
Q
What are the symptoms of Parkinson’s disease?
A
- A movement disorder, with 4 ‘cardinal’ features
- Resting Tremor
- Bradykinesia (Slow movement)
- Rigidity (Stiff like posture)
- Postural instability (Falling over)
32
Q
What are the non motor symptoms of Parkinson’s disease?
A
- > 90% of patients display additional non motor symptoms including:
- Depression & Anxiety
- Loss of smell
- Sleep disorders
- Constipation
- Dementia (less common)
- Other psychiatric complications (less common)
33
Q
What are the pathological hallmarks of Parkinson’s disease?
A
- Loss of dopaminergic neurons of the substantia nigra
- The substantia nigra is a part of the basal ganglia in the midbrain (Dark substance)
- The dark substance is due to the expression of neuromelanin
34
Q
What is the other pathological hallmarks of Parkinson’s disease?
A
- Proteinopathy
- Called Lewy bodies
- Intracellular protein aggregates
- Enriched in ã-synuclein protein
- Normal role of ã-synuclein is poorly understood (Involved in neurotransmitter release
- Lewy bodies not pathogenic, but increase ã-synuclein is
35
Q
Describe the genetic causes of Parkinson’s disease
A
- 10% of cases have a clear genetic cause
- 3 rough categories
- Early/Juvenile onset recessive mitochondrial conditions
- Late/later onset usually autosomal dominant PD
- Mutations that cause PD plus conditions
36
Q
Describe the early onset mitochondrial PD
A
- Mitochondria have a finite lifespan due to oxidative stress
- Damaged mitochondria are selectively removed from the cell by “mitophagy” - Autophagy of mitochondria
- Loss of function mutations in 2 proteins central to activating mitophagy - PINK1 and Parkin - Cause of early onset PD
- Mutations in at least 3 other genes linked to mitochondrial stress response also linked to EO PD
- Limitation is distinct from late onset sporadic PD (A whole different disease?)
37
Q
Describe the later onset genetic PD
A
- Some genetic causes found from kindred studies (like EO PD), but more limited including:
- SCNA (a synuclein) gene amplification (Confirms that a synuclein is pathogenic)
- LRRK2 gain of function
- VPS35 gain of function
- GBA loss of function
38
Q
How is GBA linked significantly to a-synuclein?
A
- GBA encodes GCase (B-glucocerebrosidase), a lysosomal enzyme
- a-synuclein is degraded in the lysosome
- They are connected via..
39
Q
What happens between GCase and lysosomes in an ordinary person?
A
- The GCase is trafficked into the lysosome
- The lysosome is then satisfied and can act as the final part for autophagy
- Where it can degrade a-synuclein so you don’t get Lewy bodies
40
Q
What happens in an individual that has a GBA mutation?
A
- These individuals have less activity of GCase so there will be less active GCase in the lysosome
- This causes the lysosome to become impaired
- Leads to a corresponding reduction in its ability to serve as the last step in autophagy
- a-synuclein is insufficiently degraded and accumulates
41
Q
What if you don’t have a GBA mutation but still have an increase in a-synuclein?
A
- The excess a-synuclein inhibits the translocation of GCase into the lysosome
- You then end up with an impaired lysosome
- This lysosome will no longer be able to act efficiently in autophagy such that you get even more of a synuclein
- This could be also known as a pathogenic feed forward loop, up a-synuclein-> down GCase -> down Lysosomal function -> a-synuclein
42
Q
How can Parkinson’s disease be linked to lysosomes?
A
- Other PD genes play roles in processes involving lysosomes
- Consistently autophagy is dysregulated in PD brain
- Problems in autophagy will also lead to mitochondrial dysfunction (decrease mitophagy)
- Endocytic pathways are a big focus in PD research
43
Q
Describe the GWAS results of Sporadic PD
A
- Risk genes
- Has shown many “cause genes” also influence risk
- Also found many new PD genes
- Now believed as much as 30% of PD risk is genetic
44
Q
What does MAPT encode?
A
Tau
45
Q
What was found from the GWAS results of sporadic PD?
A
- The linkage of MAPT to PD was a big surprise
- Neurofibrillary tangles can be found in PD brains (even in same cells as Lewy bodies) but not to a greater extent
- However: More NFTs in brains of LRRK2 PD
- Microtubules disruption long implicated in PD
46
Q
What are other risk factors for PD?
A
- Gender (more common in men)
- Red hair (2x risk)
- Head injury
- Not smoking, not consuming caffeine
- Herbicides, pesticides, insecticides
- Exposure to metals
- General anaesthesia
47
Q
What is meant by neuroinflammation?
A
- The activation of the immune system within the nervous system
- In the brain, this principally means activation of microfilm (astrocytes also involved)
48
Q
How does neuroinflammation work in neurodegenerarion?
A
- Imagine the neurone is damaged with a neurotic insult (Injury or toxins) which causes a dying/damaged neurone
- This releases factors which activates microglia
- The microglia then becomes reactive microglia which will then secretes various neurotrophic factors such as IL-1B, TNF-a, Prostaglandins
- This in turn triggers more cell damage and cell death
49
Q
Why is neuroinflammation important in neurodegeneration?
A
Produces another positive feed cycle
50
Q
How can ageing be linked to microglia?
A
- Reactive microglia can be protective of neurons or damaging
- Protective: Inflammatory or normal removal of unhealthy cells
- Damaging: Pro-inflammatory, Response to pathogens
- Ageing induces a shift towards production of damaging reactive microglia, due to changes in microglia plans gene expression (Neuroinflammaging)
51
Q
What evidence do we have of neuroinflammation as a cause?
A
- Many Alzheimer’s risks causes raised levels of circulating inflammatory cytokines:
- High BP, cardiovascular disease, diabetes, smoking
- In principal, effects can cross the blood brain barrier
- Enough to cause AD unknown
52
Q
What is the theory of Parkinson’s disease starting in the gut?
A
- Lewy bodies pathology in gut often precedes pathology in brain
- Evidence that gut inflammation is sufficient to cause gut Lewy bodies
- Spread to brain via vagus nerve
- May have a role for microbiota
53
Q
What are the other effects of ageing?
A
- Shortening of the telomeres in adult stem cells, can’t replace dying neurons
- Increased reactive oxygen species
- Other changes in gene expression: Altered Wnt signalling
- Wnts are neuroprotective and neuromodulatory
- Wnt/B-catenin is decreased in adult brain
- Deregulated wnts in developmental and geriatric neuro conditions
