Neurodegenerative diseases Flashcards
Intro to lecture
→ Whereas neural tube closure defects and the like are failures to properly assemble the nervous system, neurodegenerative diseases are the consequence of failure to maintain these structures.
→ As you will see, neurodegeneration can begin from birth, but, more often than not, neurodegenerative diseases are diseases of the elderly.
→ In a world with an increasing population size and increasing longevity, understanding age-related neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease is of growing importance.
What is neurodegeneration and neurodegenerative disease?
Neurodegeneration = neuro (relating to neurons) + degeneration (progressive loss)
Neurodegenerative disease = any disease caused by neurodegeneration
What are some basic details about neurodegenerative disease?
→ 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
→ Neurodegenerative diseases are 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 do common features of neurodegenerative diseases include?
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 and diseases frequently involve:
→ Protein aggregation (“proteinopathies”)
→ Lysosomal dysfunction
→ Mitochondrial dysfunction
→ Associated inflammation via activation of glia
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+
AD is NOT a normal part of ageing – it is a disease
What is dementia as an umbrella term?
→ A decline in memory and other cognitive functions that impair quality of life
→ Impairments in dementia are distinct from “normal” cognitive lapses, e.g. getting lost in their own neighbourhood, not recognising a family member etc
→ Normal ageing = gradual decline in normal cognition, gradual changes in personality
What are pathological hallmarks of Alzheimer’s?
Brain shrinkage
Proteinopathies:
1. Amyloid plaques
→ they are Extracellular protein aggregates
→ they are Enriched in Aβ peptides
- Neurofibrillary tangles/ paired helical filaments
→ Intracellular protein aggregates
→ Enriched in Tau protein
What is Abeta peptide?
→ Aβ peptide is cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases
→ Mutations to three proteins involved in Aβ peptide processing are known to cause rare early onset forms of Alzheimer’s:
APP
PSEN1
PSEN2
→ Since early 1990’s “Amyloid hypothesis of AD”, which states that Aβ and/or amyloid plaques are the cause of AD
What does Tau normally bind?
→ Tau (an intracellular protein) normally binds microtubules in axons
→ Hyperphosphorylated tau is displaced causing:
- Tangles
- Destabilised microtubules
What 3 main roles do microtubules have?
→ Structure/shape of cell
→ Positioning of organelles
→ Motorways for transporting vesicular cargo
In typical late onset AD (i.e. not genetic forms of AD), neurofibrillary tangles are:
→ Seen before the amyloid plaques are seen
→ Well correlated with cell death and progression
→ The Tau hypothesis suggests Tau is upstream Aβ = Tau hypothesis
So is the Tau or Amyloid hypothesis the real one?
We don’t know! Still very controversial!
What are some other risk factors for Alzheimer’s disease?
- 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 do symptoms of Parkinson’s disease include?
A movement disorder, with four ‘cardinal’ features:
→ Resting tremor
→ Bradykinesia (slow movement)
→ Rigidity
→ Postural instability (fall over)
> 90% of patients display additional NON-MOTOR symptoms, including:
→ Depression & Anxiety
→ Loss of smell
→ Sleep disorders
→ Constipation
Less common than the above but more frequent than general population:
Dementia
Other psychiatric complications
What are pathological hallmarks of Parkinson’s disease?
- Loss of dopaminergic neurons of the substantia nigra
NORMAL BRAIN SECTION
→ Neurons visible by eye due to expression of neuromelanin
PARKINSONS DISEASE BRAIN SECTION
→ Lack of pigmentation shows loss of substantia nigra
→ Histology of dopaminergic neuron loss
Proteinopathy again!
→ 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
Talk about early onset mitochondrial Parkinson’s Disease(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?)
Talk about 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
GBA has been linked to alpha-synuclein
→ GBA encodes GCase (β-glucocerebrosidase ), a lysosomal enzyme
→ α-synuclein is degraded in the lysosome
→ They are connected
→ If less GCA, lysosome is impaired, autophagy is reduced and alpha-synuclein levels increase if increased a-synuclein, lysosome becomes impaired and then leads to an increase in a-synuclein (pathogenic feed-forward loop!) = increase in alpha-synuclein= decrease in GCase= decrease in lysosomal function
Name some other risk factors of Parkinson’s Disease
- 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?
Neuroinflammation = activation of the immune system within the nervous system
Neuroinflammation amplifies the effects of neurodegeneration
Neuronal damage/death—> neurotoxic insult—> activates microglial activators (e.g. alpha-synuclein and other proteins)—> leads to activation of neurotoxic factors which brings back to neuronal damage/death - again another feedback loop
What 2 things can microglia be?
Reactive microglia can be protective of neurons or damaging:
1. 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 (neuroinflammaging)
What are some 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?!
Axon is…
the Achilles heel of a neuron
