Neurodegenerative Diseases Flashcards
Define neurodegenration
neuro (relating to neurons) + degeneration (progressive loss)
What is a neurodegenerative disease
any disease caused by neurodegeneration
What are some features of neurodegenerative diseases
Affect the CNS or PNS (or both)
Begin at any stage of life:
- The most common ones are associated with ageing
- Rarer types of neurodegenerative disease start in childhood or even from birth
- Earlier age of onset = greater genetic contribution
- Later age of onset = more likely a sporadic (or idiopathic) disease
Why are neurodegenerative diseases highly heterogeneous
- Some disease names are really umbrella terms. Conditions with overlapping phenotypes, but distinct causes (e.g. at least 25 types of SCA from mutations in different genes)
- Some diseases are inherently pleiotropic symptoms manifest differently in different people e.g. Parkinson’s disease symptoms unique to individual)
what are some common features of AD?
Many follow a similar pattern:
- Molecular impairment somewhere in the cell
- Decreased transmission at synapse
- “Dying back” of neurites (axons and/or dendrites)
- Cell death
Frequently involve:
- Protein aggregation (“proteinopathies”)
- Lysosomal dysfunction
- Mitochondrial dysfunction
- Associated inflammation via activation of glia
What are the clinical and research challenges
- Neurodegenerative diseases rarely manifest overt signs and symptoms until long after neurodegeneration has begun
Early treatment is impossible without early diagnosis
The 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 causes - Neurodegenerative diseases remain incurable
What is Alzheimer’s disease
- The most common neurodegenerative disease and the most common cause of dementia
- Onset is usually >65 years of age, but ~10% are “early onset” starting ~30s onwards
- Incidence:
10% of people aged 65+
50% of people aged 85+ - AND is NOT a normal part of ageing, it is a disease
What is dementia
- A decline in memory and other cognitive functions that impair quality of life
- Impairments in dementia are distinct from “normal” cognitive lapses
How was Alzheimers discovered
- First described by Alois Alzheimer, a German psychiatrist and neuroanatomist, in 1906/7
- Initial psychiatric and pathological observations made in younger patients
“Pre-senile dementia” - Pathology then found to be widespread in older patients
What is the 1st pathological hallmark of Alzheimer’s
Brain shrinkage
What is the 2nd pathological hallmark of Alzheimer’s
Proteinopathies:
- Amyloid plaques
Extracellular protein aggregates
Enriched in Aβ peptides - Neurofibrillary tangles
Also called paired helical filaments
Intracellular protein aggregates
Enriched in Tau protein
Describe Amyloid plaque formation
Aβ peptide is cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases:
- B-secretase
- Y-secretase
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
PSEN2
PSEN1/2 both are components of y-secretase
- Since early 1990’s “Amyloid hypothesis of AD”, which states that Aβ and/or amyloid plaques are the cause of AD
Explain tau and the formation of neurofibrillary tangles
- Tau normally binds microtubules in axons
- Hyperphosphorylated tau is displaced causing:
Tangles
Destabilised microtubules
what is the importance of microtubules in neurites
In all post-mitotic cells, microtubules have 3 main roles:
- Structure/shape of cell
- Positioning of organelles
- Motorways for transporting vesicular cargo
What is the Tau hypothesis
- In typical late onset AD (i.e. not genetic forms of AD), neurofibrillary tangles are:
Seen before amyloid plaques
Well correlated with cell death and progression - Suggests Tau is upstream Aβ = Tau hypothesis
What causes AD, amyloid or Tau
- 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?
What are the 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 is Parkinson’s disease
- The second most common neurodegenerative disease
- Onset is 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
What is the history of PD
- ‘First’ reported in 1817 by Dr James Parkinson, an East London physician
“Shaking palsy” - Identical symptoms described by a Hungarian physician, Ferenc Pápai Páriz, in 1690.
- However, the similar observations stretch back to ancient Egypt.
What are the symptoms of PD
- A movement disorder with four cardinal features
1) Resting tremor
2) Bradykinesia
3) Rigidity
4) Postural instability
what are the non-motor symptoms of PD
90% of patients display additional non-motor symptoms, including:
- Depression & Anxiety
- Loss of smell
- Sleep disorders
- Constipation
These are more common
- Dementia
- Other psychiatric complications
Less common symptoms
what are one pathological hallmarks of PD
- Loss of dopaminergic neurone of the substation nigra
- Lack of pigmentation shows loss of substantia nigra
What is another pathological hallmark of PD
Proteinopathy
- Lewy bodies
Intracellular protein aggregates
Enriched in α-synuclein protein - Normal role of α-synuclein is poorly understood (involved in neurotransmitter release)
- Lewy bodies not pathogenic, but ↑ α-synuclein is
What are the genetic causes of PD
10% of cases have a clear genetic cause
Three rough categories:
- Early/Juvenile-onset recessive mitochondrial conditions
- Late/later-onset (usually) autosomal dominant PD
- Mutations that cause “PD-plus” conditions
Explain 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 (whole different disease?)
Explain 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 & α-SYNUCLEIN connected
- GBA encodes GCase (β-glucocerebrosidase ),a lysosomal enzyme
- α-synuclein is degraded in the lysosome
Explain the mechanism how GBA & α-SYNUCLEIN are linked
Normally α-SYNUCLEIN is broken down in lysosomes by GCase which is transported in from Golgi/ER
When there is reduced GCase there is less degradation of a-syn.
There is increased a-syn which results is the formation of lewy bodies
Explain the pathogenic feed-forward loop
Increases a-syn can inhibit the transport of Gcase into lysosomes which leads to less breakdown of a-syn. Further feeds into the cycle
What is the link between autophagy and PD
- 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
What are risk genes in PD
- 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
How is Tau linked to PD
- Linkage of MAPT to PD was a big surprise
- Neurofibrillary tangles can be found in PD brains (even in the same cells as Lewy bodies), but not to any great extent
However:
- More NFTs in brains of LRRK2 PD
- Microtubule disruption long implicated in PD
What are the other risk factors of 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 neuroimmflamation
Activation of the immune system within the nervous system
In the brain, this principally means activation of microglia (astrocytes are also involved)
How are microglia ‘reactive”
- Amoeboid shape
- More motile
- Production of cytokines
- (Eventually) Phagocytic
How is neurodegeneration mediated by neuroinflammation
- A neurone experiences injury, toxins or gene mutations
- Microglial activators such as a-syn and other protein are released from neurones which activate microglia
- Neurotoxic factors are released from microglia
- The neurone dies
How is aging and microglia related
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
How can the normal function of neuroinflammation be altered
External triggers such as AB, environmental toxins and pathogens can activate microglia which can cause neuronal death
How can neuroinflammation be a cause of Alzheimers and 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
But an interesting story emerging in PD…
Explain how gut inflammation cause PD
- 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?
What are the other effects of ageing
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?!
