Neurodegenerative disease Flashcards
What is neurodegeneration?
The progressive loss of neurones (CNS, PNS or both)
Neurodegenerative diseases are highly heterogeneous
Some disease names are really umbrella terms:
> conditions with overlapping phenotypes but different causes
Some diseases are inherently pleiotropic
> symptoms manifest differently in different people
Common features in the process of a neurodegenerative disease
Many follow a similar pattern: > molecular impairment somewhere in the cell > Decreased transmission at synapse > "Dying back" of neurites > Cell death
Common features involved in neurodegenerative disease?
Frequently involve: > Protein aggregation > Lysosomal dysfunction > mitochondrial dysfunction > associated inflammation via activation of glia
Challenges of treating a neurodegenerative disease
They rarely manifest overt signs and symptoms until long after neurodegeneration has begun
> early treatment s impossible without 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 understand the causes
They remain incurable
What is dementia
A decline in memory and other cognitive functions that impair a person’s quality of life
How does dementia differ from normal loss of memory
What are pathological hallmarks of Alzheimer’s disease
Brain shrinkage
Proteinopathies
>Amyloid plaques
-Extracellular Protein aggregates
-Enriched in Aβ peptides
> Neurofibrillary tangles
- also called paired helical filaments
- intracellular protein aggregates
- Enriched in Tau protein
What are Aβ peptides
Aβ peptide is cleaved from a transmembrane protein called amyloid beta precursor protein
What is the Amyloid hypothesis?
Mutations to three proteins involved in Aβ peptide processing are known to cause rare early onset forms of Alzheimer’s:
- APP
- PSEN1 and PSEN2 (Presenilin-1 and Presenilin-2; both a components of γ-secretase)
What are Tau and neurofibrillary tangles?
- Tau normally binds microtubules in axons
-Hyperphosphorylated Tau is displaced causing:
> Tangles
> Destabilised microtubules
Why are microtubules important in neurites?
The 3 main roles of microtubules are:
- Structure/shape
- Positioning of organelles
- Motorways for transporting vesicular cargo
What is a neurones achilles heel?
Distance between axon terminal and nucleus
What is the Tau Hypothesis?
neurofibrillary tangles are:
- Seen before amyloid plaques
- well correlated with cell death and progression
suggests Tau is upstream Aβ = Tau hypothesis
Which hypothesis is the right one?
Probably more evidence for amyloid, but…
- Therapies based on inhibiting Aβ aggregation so far haven’t worked
Tangles and plaques may be red herrings
- Are they pathogenic or by-standers? Or even protective?
- Oligomeric forms of Aβ and tau are more likely to be pathogenic
Could both be downstream of other factors?
Other risk factors of AD
- 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 (APOE gene status most significant)
What are the motor symptoms of Parkinsons?
A movement disorder with four ‘cardinal’ features:
- Resting tremor
- Rigidity
- Bradykinesia (slow movement)
- Postural instability (fall over)
Non-motor symptoms of Parkinsons
All fairly common:
- Depression and anxiety
- Loss of smell
- Sleep disorders
- Constipations
less common:
- Dementia
- other psychiatric complication
What are of pathological hallmarks of PD?
Loss of dopaminergic neurones of the substantia nigra (basal ganglia in the midbrain)
*other brain regions are also affected
Proteinopathy
-Lewy bodies
>Intracellular protein aggregates
> Enriched in α-synuclein protein (involved in neurotransmitter release)
Lewy bodies not pathogenic, but ↑ α-synuclein is
Describe the genes involved in PD
They fall into 3 categories:
- Earlyonset recessive mitochondrial conditions
- Late autosomal dominant PD
- Mutations that cause “PD-plus” conditions
What causes early onset mitochondrial PD?
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 two proteins central to activating mitophagy – PINK1 and Parkin – cause EO PD
Mutations in at least 3 other genes linked to mitochondrial stress responses also linked to EO PD
Limitation: this PD is distinct from late-onset sporadic PD (a whole different disease?)
Describe the causes of late onset Genetic PD
Some genetic causes found from kindred studies (like EO PD), but more limited, including: SNCA (α-synuclein) gene amplification Confirms that α-synuclein is pathogenic LRRK2 gain-of-function VPS35 gain-of-function GBA loss-of-function
How is GBA linked to α-synuclein
GBA encodes GCase (β-glucocerebrosidase ),a lysosomal enzyme
α-synuclein is degraded in the lysosome
They are connected…
How are PD and lysosomes linked?
- Other PD genes play roles in processes involving lysosomes
- Consistently, autophagy is dysregulated in PD brains.
- Problems in autophagy will also lead to mitochondrial -dysfunction (↓ mitophagy)
- Endocytic pathways are a big focus in PD research
Tau and PD
- Neurofibrillary tangles can be found in PD brains
- More NFTs in brains of LRRK2 PD
- microtubule disruption long implicated in PD
Risk factors for PD
- Gender (more common in men)
- Red hair (~2x risk)
- Head injury
- Not smoking, not consuming caffeine
- Herbicides, pesticides, insecticides
- Exposure to metals (i.e. welder)
- General anaesthesia
What is Neuroinflammation?
activation of the immune system within the nervous system
In the brain, this principally means activation of microglia
What happens to Microglia when it is activated?
- It becomes ‘reactive’ Microglia
- Amoeboid shape, loss of arms
- becomes more motiles
- production of cytokines
- eventually phagocytic
Describe the cyclical process of Neuroninflammation
Positive feedback cycle
What effects does ageing have on microglia?
Reactive microglia can be protective of neurons or damaging
Protective
- anti-inflammatory, e.g. TGFβ
- normal removal of unhealthy cells (i.e. homeostasis)
Damaging
- pro-inflammatory, e.g. IL-1, TNF-α
- response to pathogens etc(i.e. damage to neurons = ‘collateral damage’)
Aging induces a shift towards production of damaging reactive microglia, due to changes in microglial gene expression
Could neuroinflammation be a cause of PD?
Many Alzheimer’s risk factors cause 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? Not known
PD Gut to brain?
Lewy body 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?
Role for microbiota?
Other effects of ageing on neurodegeneration?
Shortening of telomeres in adult stem cells
Increased reactive oxygen species
Other changes in gene expression
- Altered Wnt signalling is a big focus in AD and PD
- Wnts are neuroprotective and neuromodulatory
- Wnt/β-catenin is decreased in adult brain
- Deregulated Wnts in developmental and geriatric neuro conditions?!
