Neurodegenerative diseases Flashcards
What does neurodegenerative diseases affect? When can it occur?
Affects the CNS or PNS
At any stage of life
- Most common ones associated with ageing
- rarer types begin in childhood or birth
- earlier onset = greater genetic contribution
- later onset = more likely sporadic or idiopathic disease
What similar pattern do neurodegenerative diseases follow?
- Molecular impairment somewhere in the cell
- Decreases transmission at synapse, first symptom/place impairment manifests
- From the synapse there is “dying back” of neurites (Axons and/or dendrites) - ultimately progresses back to cell body
- Leads to cell death
When is onset of Alzheimers? What does it cause?
What are the symptoms?
Onset >65 years of age, 10% of cases are early onset, 30 years onwards.
Most common cause of dementia
Decline in memory and other cognitve functions that impair quality of life.
Sudden changes in personality, changes of mood.
What are the pathological hallmarks of alzheimers?
Brain damage, brain has shrunk. The cerebral cortex, hippocampus shrink. Sulci appear deeper. Ventricles enlarge.
Proteinopathies, aggregation of proteins.
- Amyloid plaques- round bodies that sit outside the cell. Extracellular protein aggregates enriched in A beta peptides
- neurofibrillary tangles are within the cell, also called helical filaments. Intracellular protein aggregates enriched in Tau protein.
Where is A beta peptide cleaved from?
A transmembrane protein, amyloid beta precursor protein (APP) by proteases.
Fragment corresponding to A beta is outside cell.
Beta-secretase and then y-secretase cleave APP, releasing A beta fragment that accumulates and forms amyloid plaque outside cell.
What is the amyloid hypothesis?
Mutations to three proteins involved in AB peptide processing are known to cause rare early onset forms of Alzheimer’s
- APP gene
- PSEN1
- PSEN2
Presenilin-1 and 2 both are components of y-secretase
Since early 1990’s Amyloid hypothesis of AD which states that AB and/or amyloid plaques are the cause of AD
What does tau displacement cause?
Tau normally binds microtubules in axons
Hyperphosphorylated (by kinases and serine, threonine and tyrosine) tau is displaced causing
- Tangles
- Destabilised microtubules
What are the 3 main roles of microtubules in post-mitotic cells?
Structure/shape of cell, holding plasma membrane in place
Positioning of organelles
Motorways for transporting vesicular cargo e.g proteins, lipids going between organelles and across the cell
What is the tau hypothesis?
In typical late onset AD (not genetic forms of AD), neurofibrillary tangles are:
- Seen before amyloid plaques
- Correlated with cell death and progression of disease e.g advanced Alzheimer’s will have lots of tau. Where cell death is and tangles are is correlated with the domains of cognition that are affected.
Suggests Tau is upstream AB peptide = Tau hypothesis
Effects of Tau causes those in AB
What are risk factors for AD?
Down syndrome (APP is on chromosome 21)
High BP, cardiovascular disease, diabetes
Gender (more common in women)
Low education, education provides cognitive reserve
Head injury, trauma
Smoking and drinking
Only a small genetic risk contribution for late-onset AD (APOE gene status most significant)
When is onset of Parkinson’s disease?
60-65 years of age, 10% before 45.
Lifetime risk of males 2%, females 1.3%
What are the symptoms of Parkinson’s?
Movement disorder with four cardinal features
- Resting tremor, present when person isn’t doing anything. Begins in one side of body, then goes to feet and then to the other side
- Bradykinesia (slow movement)
- Rigidity
- Postural instability (fall over)
Younger patients tend to get resting tremor first, patients who develop it later in life it manifests with bradykinesia and rigidity.
What are the non-motor symptoms of Parkinson’s?
>90% of patients display additional non-motor symptoms including:
Depression and anxiety
Loss of smell
Sleep disorders
Constipation
Dementia
Other psychotic complications
What are the pathological hallmarks of Parkinson’s?
Loss of dopaminergic neurones of the substantia nigra – neurones that produce dopamine.
- Substantia nigra is part of basal ganglia in midbrain – means dark substance – neuromelanin is dopaminergic neurones of substantia nigra
- In Parkinson’s, there is lack of pigmentation, shows loss of dopaminergic neurones in substantia nigra
What is the other hallmark of PD?
Proteinopathy.
Lewy bodies
- intracellular protein agrgegates
- enriched in a-synuclein protein
- lewy bodies not pathogenic but increase in a-synuclein is
What three categories do genes in famiilal PD fall under?
Early/juvenile-onset recessive mitochondrial conditions – autosomal recessive mutations
Late/later-onset (usually) autosomal dominant PD
Mutations that cause “PD-plus” conditions - rare
What causes early onset mitochondrial PD?
Mitochondria have a finite lifespan due to oxidative stress - damaged
Damaged mitochondria are selectively removed from the cell by mitophagy – autophagy of mitochondria – components can be recycle and reused
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
What are some genetic causes of PD?
SNCA (a-synuclein) gene amplification – mutation, linked to genetic forms of PD
- Confirms that a-synuclein is pathogenic
LRRK2 gain-of-function mutation
VPS35 gain-of-function mutation
GBA loss-of-function mutation - a dominant loss of function, these patients are carriers of a recessive mutation. If they had both copies, they would get Gaucher disease, a type of lysosomal storage disorder.
How is GBA functionally linked to a-synuclein?
GBA encodes GCase (B-glucocerebrosidase), a lysosomal enzyme
A-synuclein is degraded in the lysosome
They are connected
What does a mutation in GBA or GCase cause?
Normally GCase is trafficked into lysosome from other organelles, acts as final part of autophagy and mitophagy, degrades a-synunclein so there is no accumulation, no lewy bodies, no PD.
With mutation there is less active GCase in lysosome, lysosome is impaired. Can’t function in autophagy, a-synuclein accumulates.
What does excess a-synuclein due to other mutations/ sporadic PD cause?
Excess inhibits translocation of GCase into lysosome
Impaired lysosome unavle to act efficiently in autophagy, more accumulation of a-synuclein
Pathogenic feedforward loop:
- Increase a-synuclein
- decreases GCase translocation into lysosome
- decreases lysosomal function carrying out autophagy
- leading to more a-synuclein
both increased a-synunclein and decreased lysosomal function cause cell death
What are other risk factors for PD?
Gender (more common in men)
Red hair (2x risk)
Head injury
Not smoking, not consuming caffeine
Herbicides, pesticides, insecticides typically those that impair mitochondria
Exposure to metals e.g welder, likely to inhale metal
General anaesthesia
What is neuroinflammation? What are reactive microglia?
Neuroinflammation = activation of the immune system within the nervous system
In the brain this principally means the activation of microglia (Astrocytes also involved).
Reactive microglia
- Amoeboid shape
- More motile in that shape
- Production of cytokines
- Eventually phagocytic and able to engulf bits of cellular debris and pathogens
How does microglia cause neuroinflammation?
Neuronal death causes neurone to release factors e.g a-synuclein, which activate microglia.
Microglia secrete neurotoxic factors e.g IL-1B, TNF-a, prostaglandins
Triggers more cell damage and death
Positive feed forward cycle, neuroinflammaton amplifies effects of neurodegeneration
How are microglial protective of neurons?
Release anti -inflammatory cytokines e.g TGFB
Homeostatic role, normal removal of unhealthy cells without causing further injury to the host
How are microglia damaging of neurones?
What does ageing induce?
Pro-inflammatory cytokines e.g IL-1, TNF-a
Response to pathogens etc ie. Damage to neurons = collateral damage , price worth paying to avoid something else such as dying from a pathogen infection
Ageing causes shift towards production of damaging reacting microglia due to changes in microglia gene expression - neuroinflamation
What are the other effects of ageing?
Shortening of telomeres in adult stem cells, not able to replace dying neurones as well
Increase in reactive oxygen species with ageing, increasing stress on neurones
Other changes in gene expression:
- Altered Wnt signalling is a big focus in AD and PD
- Wnt ligands are neuroprotective and neuromodulatory, stop neurones from dying – play role in cognition
- Wnt/B-catenin is decreased in adult brain
- Deregulated Wnts in developmental and geriatric neuro conditions?!
