Neurodegenerative Diseases Flashcards
Define neurogeneration
Progressive loss of neurons
Define Neurodegenerative disease
Any disease caused by neurodegeneration
What are some patterns with neurogenerative diseases based on the age of onset?
Earlier age of onset = greater genetic contribution
Later age of onset = more likely a sporadic
What are the characteristics of neurodegenerative diseases?
Highly heterogenous
- some disease names are really umbrella terms
- some diseases are inherently pleiotropic
What are the common features of neurodegenration?
- Molecular impairment somewhere in the cell
- Decreased transmission at synapse
- “Dying back” of neurites (axons or dendrites)
- Cell death
What is defined as a neurones “Achilles heal”?
Distance between the axon terminal and nucleus
What do neurodegenerative diseases frequently involve?
Protein aggregation
Lysosomal dysfunction
Mitochondrial dysfunction
Associated inflammation via activation of Glia
Why is it hard to treat and research neurodegenerative diseases?
They rarely manifest overt signs and symptoms until long after neurodegeneration has begun
- early treatment is impossible without early diagnosis
- therapeutic challenge is considerable
Studies of affected tire is very difficult until death
Remain incurable
What is Alzheimer’s?
Most common neurodegenerative disease and most common cause of dementia
Onset usually >65
What is dementia?
A decline in memory and other cognitive function that impair quality of life.
Eg. Lost in own neighbourhood or recognise faces of family members
NOT NORMAL AGEING
What are the pathological hallmarks of Alzheimer’s?
Brain shrinkage
Proteinopathies
- amyloid plaques
(Extracellular protein aggregates)
(Enriched in A-beta peptides) - neurofibrillary tangles /helical filaments
(Intracellular protein aggregates)
(Enriched in Tau protein)
What is A-beta?
Peptide cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases
What mutation involved in A-beta peptide processing are thought to cause rare early onset forms of Alzheimer’s?
APP gene
PSEN 1 gene - presenile 1
PSEN2 gene - presenile 2
What is tau?
A protien that normally binds to axons in microtubules
What is the function of tau?
Hyperphosphorylated and becomes displaced
- forms tangles
- forms destabilised microtubules (as it detaches)
What are the 3 main roles of microtubules in post-mitotic cells?
- structure/shape of cell
- positioning of organelles
- motorways for transporting vesicular cargo
In typical late onset Alzheimer’s disease what is observed?
- neurofibrillary tangles are seen before amyloid plaques
- neurofibrillary tangles are well correlated with cell death and progression
What is the Tau hypothesis?
Suggests Tau is upstream A-Beta
Why are scientists debating weather amyloid or Tau have a bigger contribution to Alzheimer’s?
- more evidence for amyloid HOWEVER therapies inhibiting A beta aggregation haven’t worked
So far - tangles and plaques may be red herrings (could be pathogenic, or by standers or even protective)
What are risk factors of developing Alzheimer’s?
Down syndrome (APP on chromosome 21)
Gender (more in women)
High BP, cardiovascular disease, diabetes
Low education
Head injury
Smoking and drinking
- only a small genetic risk condition for late onset
What is Parkinson’s disease?
Second most common neurodegenerative disease
A movement disorder
Usually 60-65 years
What are the motor symptoms of Parkinson’s?
- resting Tremor (trembling hands and feet)
- Bradykinesia (slow movement)
- Rigidity
- postural instability (fall over)
What are the non motor symptoms of Parkinson’s disease?
Depression + Anxiety
Loss of smell
Sleep disorders
Constipation
Dementic
What are the pathological hallmarks of Parkinson’s?
Loss of dopaminergic neurons of the substantial nigra (part of basal ganglia in midbrain).
Proteinopathy - Lewy bodies
Intracellular protein aggregates
Enriched in a synuclein protein
Are Lewy bodies pathogenic in Parkinson’s?
No but the increased a-synulein protein is
What genes are associated with causing Parkinson’s?
Early/Juvenile-onset recessive mitochondrial conditions
Late/later onset autosomal dominant PD
Mutations that cause “PD-plus” conditions
Describe what occurs during early onset mitochondrial PD?
Mitochondria have a finite lifespan due to oxidative stress
Loss of function mutation in two proteins central to activating mitophagy - PINK1 and Parkin
Limitation: this PD is distinct from late onset sporadic Parkinson’s (a whole different disease?)
Describe what occurs during late onset genetic PD?
S-synuclein Gene amplification
- confirms a-synuclein is pathogen and a cause of Parkinson’s
LRRK2 gain of function
VPS35 gain of function
GBA loss of function
VERY SIMILAR TO SPORADIC PARKINSON’S
Describe the correlation of GBA and alpha-synuclein.
GBA encodes GCase, a lysosomal enzyme
Alpha-synulein is degraded in the lysosome
And they’re connected - LESS ACTIVE GCase means accumulation of alpha-synuclein
OR alpha-synuclein inhibits the activation of GCase
What happens in the pathogenic feed forward loop of Parkinson’s?
Increased alpha-synuclein
Decreased GCase
Decreased lysosomal function
What are risk genes of Parkinson’s?
Has shown many “cause genes” influence risk
Found many new PD genes
Now believed as much as 30% of PD risk is genetic
What is the link between Tau and PD?
More neurofibrillary tangles are found in people with brains of LRRK2 PD
Microtubules disruption long implicated in PD
May not be enough to cause Parkinson’s by itself
What are the risk factors of Parkinson’s?
Gender (more in men)
Red hair. (X2 risk)
Head injury
Not smoking, not consuming caffeine,
Herbicides, pesticides, insecticides
Exposure to metals
General anaesthesia
What is neuroinflammation?
Activation of immune system within the nervous system.
Activation of microglia in the brain
What is the structure and function of “reactive” glia?
Ameboid shape
More motile
Production of cytokines
Eventually become phacogytic
Describe how neurodegeneration can cause neuroinflammation.
- A neurotoxic insult (injury, gene mutations, toxins) cause neuronal death/damage
- Microganglial activators (alpha-synuclein) are released from the damaged neurones
- This activates micro glia
- Micro glia then release neurotoxic factors (IL-1B, prostaglandins, and TNF-alpha )
How can reactive micro glia be protective?
- anti inflammatory cytokines released (TGF beta)
- normal removal of unhealthy cells (homeostasis)
How can micro glia be damaging?
- pro inflammatory cytokines released (TNF alpha, IL-1)
- response to pathogens (damage to neurones = collateral damage)
What is neuroflammaging?
Ageing induces a shift toward productions of damaging micro glia due to changes in micro glial gene expression.
What are some external triggers of neural glia activation?
A beta
Enviomental toxins
Pathogens
Can neuroinflammation cause Alzheimer’s?
Many Alzheimer’s risk factors cause raised levels of inflammation
In principal, effects can cross the blood brain barrier
Doesn’t cause Alzheimer’s
Explain the theory that Parkinson’s cause be caused from gut to brain signalling
Evidence suggests that gut inflammation is sufficient to cause gut Lewy bodies
Spread to vein by vagus nerve?
Could be a cause for increased constipation with Parkinson’s
What are other effects of aging 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/beta catenin in signalling pathway is decreased in adult brain
- Deregulated Wnts in developmental and geriatric
