Neurodegenerative Diseases Flashcards
What is neurodegeneration?
The progressive loss of neurons
What part of the nervous system do neurodegenerative diseases affect?
CNS, PNS or both
When do neurodegenerative diseases begin?
At any time
What does an earlier age of onset mean?
Greater genetic contribution
What does a later age of onset mean?
More likely sporadic disease
What is the common pattern of most neurodegenerative diseases?
Molecular impairment in the cell
Decreased transmission at synapse
Dying back of neurites
Cell death
What do neurodegenerative diseases frequently involve?
Protein aggregation
Lysosomal dysfunction
Mitochondrial dysfunction
Associated inflammation via activation of glia
What are some of the clinical/ research issues in neurodegenerative diseases?
Rarely manifest obvious symptoms until pathology is severe
Study of affected tissue is tricky until after death
Remains incurable
What is the most common neurodegenerative disease?
Alzheimers
When is normal onset of alzheimers?
> 65 yrs
What proportion of alzheimers are early onset and when is this?
10%
30s onwards
What proportion of people have alzheimers aged 85+?
50%
What characterises dementia?
Decline in memory and other cognitive functions that impair quality of life
What is ‘normal ageing’?
Gradual decline in normal cognition, gradual changes in personality
What are some pathological hallmarks of dementia?
Brain shrinkage
Proteinopathies
What types of proteinopathies are present in dementia?
Amyloid plaques
Neurofibrillary tangles
What are amyloid plaques enriched in?
A beta peptides
What is another name for neurofibrillary tangles?
Paired helical filaments
What is A beta?
Peptide cleaved from amyloid beta precursor protein which accumulates to form a plaque
What are neurofibrillary tangles?
Intracellular protein aggregates that are enriched in Tau protein
What is the amyloid hypothesis?
A beta and/or amyloid plaques are the cause of alzheimers
What are the three protein mutations involved in the amyloid hypothesis?
APP, PSEN1 and PSEN2
What are PSEN1 and 2 both components of?
Gamma secretase
What does tau normally do?
Binds microtubules in axons
What does displacement of hyperphosphorylated tau cause?
Tangles and destabalised molecules
What are the three main roles of microtubules in post-mitotic cells?
Structure/ shape of a cell
Positioning of organelles
Motorways for transporting vesicular contents
Why is the tau hypothesis plausible?
In typical late onset alzheimers, neurofibrillary tangles are seen before amyloid plaques and well correlated with cell death and progression
What does the tau hypothesis suggest?
Tau is upstream of A beta
What are some other risk factors for alzheimers?
Down syndrome Gender (women) High BP, CVD and diabetes Low education Head injury Smoking and drinking Small genetic risk contribution
What is the second most common neurodegenerative disease?
Parkinsons
What is the average age of parkinsons disease onset?
60-65 yrs
What are the motor symptoms in parkinsons?
Resting tremor
Bradykinesia
Rigidity
Postural instability
What are the non-motor symptoms of parkinsons?
Depression and anxiety Loss of smell Sleep disorders Constipation Dementia
What are some of the pathological hallmarks of parkinsons?
Loss of dopaminergic neurons of the substantia nigra
Proteinopathies (Lewy bodies)
What are lewy bodies?
Intracellular protein aggregates enriched in alpha-synuclein protein
Are lewy bodies pathogenic?
No
What are the three rough categories for causes of parkinsons?
Early onset autosomal recessive mitochondrial conditions
Late onset autosomal dominant
Mutations that cause ‘parkinsons plus’ conditions
What causes Early onset autosomal recessive mitochondrial conditions?
Loss of function mutations in PINK1 and parkin cause decreased mitophagy
What does autosomal dominant parkinsons cause?
Alpha synuclein gene amplification
LRRK2 gain of function
VPS35 gain of function
GBA loss of function
What does GBA encode?
GCas - a lysosomal enzyme
Where is alpha synuclein degraded?
In the lysosome
What is the pathogenic feed-forward loop?
Alpha-synuclein inhibits the transport of GCas into the lysosome, which decreases lysosomal function
How much of parkinsons is genetic?
30%
What are the risk factors for parkinsons?
Gender (men) Red hair Head injury Not smoking/consuming caffeine Herbicides, pesticides, insecticides Exposure to metals General anaesthesia
What is neuroinflammation?
Activation of the immune system within the nervous system
What are the features of reactive microglia?
Amoeboid shape
More motile
Production of cytokines
Eventually phagocytic
How does neuroinflammation cause neurodegeneration?
Neurotoxic insult (causing neuronal damage/death)
Release of microglial activators
Reactive microglia release neurotoxic factors like IL-1B, TNF-alpha and prostaglandins
What can reactive microglia cause?
Protection or damage of neurons
How are reactive microglia protective of neurons?
Anti-inflammatory cytokine release -> contributes to normal removal of unhealthy cells
How can reactive microglia be damaging to neurons?
Proinflammatory cytokine release in response to pathogens
What does ageing induce a shift towards?
Production of damaging reactive microglia due to changes in microglia expression
What can microglia be activated by?
External triggers (Abeta, environmental toxins and pathogens)
What precedes lewy body pathology in brain?
Lewy body pathology in the gut
What are some effects of ageing?
Shortening of telomeres in adults
Increased reactive oxygen species
Changes in gene expression (decreased wnt beta catenin pathway in adult brain)
