neurodegenerative diseases Flashcards
Define neurodegeneration
- neuro = relating to neurons
- degeneration = progressive loss
what are some basic details of neurodegenerative disease?
- affect both CNS and PNS
- associated with ageing
- onset at earlier age = greater genetic contribution
- highly heterogenous
- conditions with overlapping phenotypes but distinct causes.
- some diseases are inherently pleiotropic (produce more than one effect)
- symptoms of same condition different in different individuals, eg: Parkinson’s disease
What are common features of neurodegenerative disease?
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
what is ‘achilles heel’
-distance between nucleus and axon terminal
what do neurodegenerative disease frequently involve?
- protein aggregration (protienpathies)
- lysosomal dysfunction
- mitochondrial dysfunction
- associated inflammation via activation of glia
What are features of Alzheimer’s disease?
- most common cause of dementia
- onset >65 y/o
- incidence : 10% of ppl aged 65+ , 50% aged 85+
- AD is NOT a normal part of aging it is a disease
What is dementia?
- decline in memory and other cognitive functions that impair quality of life
- impairments in dementia are distinct from ‘normal’ cognitive lapses.
What is the history of Alzheimer’s?
- Alios Alzhiemers , German psychiatrist, 1906
- initial psychiatric and pathological observation made in younger patients “pre-senile dementia”
- pathology then found in older patients
What are pathological hallmarks pf AZ?
- brain shrunk
- proteinpathies :
(a) amyloid plaques- extracellular protein aggregates
- enriched in A beta peptides
(b) neurofibrillary tangles - also called paired helical filaments
- intracellular protein aggregates
- enriched in tau protein
- enriched in A beta peptides
- extracellular protein aggregates
What is A beta?
- A beta peptide is cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases (beta secretase and gamma secretase)
- cleaved amines accumulate and form amyloid beta precursor protein.
What is the amyloid hypothesis?
- mutations to three proteins involved in A beta peptide processing are known to cause rare early onset forms of alzheimer’s
- APP = beta secreteaste
- PSEN1 and PSEN2 both components of gamma secretase
- since early 1990s “amyloid hypothesis of AD” states that A beta and amyloid plaques are the cause of AD
How does tau and neurofibrillary tangles lead to cell death?
- tau normally binds microtubules in axons
- hyperphosphorylated tau is displaced causing :
tangles and destabilised microtubules - this leads to neuronal death
What are 3 main roles of microtubules in all post-mitotic cells?
- structural/shape of cell
- positioning of organelles
- motorways for transporting vesicular cargo
What is tau hypothesis?
- in typical late onset AD (ie: not genetic forms of AD), neurofibrillary tangles are:
- seen before amyloid plaques
- well correlated with cell death and progression - suggests Tau is upstream A beta = tau hypothesis
What are other risk factors of Az?
- down syndrome
- gender
- high BP, CVS, diabetes
- low education
- head imjury
- smoking and drinking
What is the history of parkinsons disease (PD)?
- first reported in 1817 by DR James
- “shaking palsy”
- identical symptoms identified by hungarian physician in 1690
What are symptoms of parkinsons?
- movement disorder, with 4 cardinal features:
1. resting tremor
2. bradykinesia (slow movement)
3. rigidity
4. postural instability (fall over)
What are non motor symptoms?
- > 90% of patients displat additional non-motor symptoms, including:
-depression - loss of smell
- sleep disorders
- constipation
less common : - dementia and other psychiatric complications.
what are 2 pathological hallmarks of PD?
- loss of dopaminergic neurons of substania nigra
-dopaminergic = neurons that produce the neurotransmitter dopamine
-substantia nigra = “dark substance” part of basal ganglia in the midbrain
=> PD does NOT only affect dopaminergic neurons of the substansia nigra - other brain regions are also affected hence why we have other symptoms. - Proteinopathy
- lewy bodies :
intracellular protein aggregates
-enriched in a - synuclein protein
-normal role of a synuclein is involved in NT release
What differences can you observe in a normal brain section and PD brain section?
- normal section
- neurons visible by eye due to expression of neuromelanin - PD brain section
- lack of pigmentation, shows loss of substantia nigra
What are genetic causes of PD?
~10% of cases have clear genetic cause
- 3 rough categories
1. early/juvenile - onset recessive mitochondrial conditions
2. late/later onset (usually) autosomal dominant PD
3. Mutations that cause “PD-plus” conditions.
What are features of early onset of mitochondrial parkinsons disease?
- 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.
- loss of 3 other genes linked to mitochondrial stress responses also linked to early onset of PD.
What are limitations of early onset mitochondrial PD?
-PD is distinct from late-onset sporadic PD (a whole different disease)
What are examples of late onset genetic PD?
- SNCA (alpha- synuclein) gene amplification
- LRRK2 gain of function
- VPS35 gain of function
- GBA loss of function
How are GBA and alpha - synuclein involved in PD?
- GBA encodes GCase (beta -glucocerebrosidase) which is a lysosomal enzyme that breaks down alpha synuclein in the lysosome.
- In healthy individuals GCase is transported/trafficked from glogi/ER into lysosome where alpha synuclein will degrade it.
- accumlation of alpha synuclein leads to PD.
What happens when a mutation leads to decrease in GCase?
- less GCase transported into lysosome
- less autophagy
- lysosome degrades
- accumulation of a-Syn
What happens if you have increase in alpha synuclein due to sporadical mutation?
- excess alpha synuclein inhibits the trasnport of GCase into lysosome
- lysosome degrades
- less alpha synuclein breakdown by lysosome so even more accumulation of alpha synuclein
What is the pathogenic feed forward loop/positive loop?
- increased alpha synuclein inhibits GCase transport
- decreases GCase
- decreased lysosomal function
so even less alpha synuclein degraded
What is the pathogenic feed forward loop/positive loop?
- increased alpha synuclein inhibits GCase transport
- decreases GCase
- decreased lysosomal function
so even less alpha synuclein degraded
=> cell death
What is the role of other PD genes and how is it linked to lysosomes?
- other genes play a role in processes involving lysosomes
- consistently , autophagy is dysregulated in PD brains
- problems in autophagy will also lead to mitochondrial dysfucntion (decreased mitophagy)
- endocytosis pathway are area of research.
What has GWAS of sporadic PD discovered?
- risk genes , influence risk
- also found many new PD genes
- now believed as much as 30% of PD risk is genetic
what is the link between Tau and PD?
- reduce ability of cells to traffick vesicles make them more sensitive to PD/
What are other risk factors?
- gender (more common in men)
- Red hair
- Head injury
- not smoking, not consuming alcohol
- herbicides, pesticides , insecticides
- exposure to metals
- general anesthesia
Define neuroinflamation
- activation of the immune system within the nervous system
- in the brain, this principally means activation of microglia (astrocytes are also involved)
What are features of ‘reactive microglia’?
- amoeboid shape
- more motile
- production of cytokines
- phagocytic
How does neuroinflammation in neurodegeneration occur and amplify due to positive feedback loop?
- neurotoxin leads to neuronal damage
- this releases factors which activates microgilia (a-synuclein and other proteins are activators)
- reactive microglia releasese neurotoxic factors such as IL-1B, TNF-a, prostaglandins which trigger more cell damage and cell death(positive feedback)
How can microglia be both protective and damaging?
- reactive microglia can be protective of neurons or damaging
- protective :
=>anti-inflammatory eg TGFb
=> normal removal of unhealthy cells (ie. homeostasis)
-damaging
=> proinflamatory , eg: IL-1 , TNF - a
=> response to pathogens etc (damage to neurons = ‘collateral damage”)
How does ageing and microglia relate?
-aging induces shift towards production of damaging reactive microglia, due to changes in microglia gene expression (neuroinflammaging)
What are external triggers that activate microglia?
- A beta
- environmental triggers
- pathogens
Can neuroinflammation be the cause of Alzhiemers?
- alzhiemers risk factors cause increased levels of circulating inflammatory cytokines
- high BP, Cardiovascular disease, diabetes, smoking
- effects can cross the blood -brain barrier
- enough to cause AD
How does gut inflammation cause damage in brain leading to PD?
- Lewy body pathology in gut often preceded pathology in brain
- Evidence that gut inflammation is sufficient to cause gut Lewy bodies
- spread to brain via vagus nerve
What are other effects of aging?
- shortening of telomeres in adult stem cells
- increased reactive oxygen species
- other changes:
=>altered Wnt signalling is a big focus in AD and PD
=> Wnts are neuroprotective and neuromodulatory
=> wnt/ beta- catenin is decreased in adult brain
=> Deregulated Wnts in developmental and geriatric neuro conditions.
What are the challenges of studying neurodegenerative disease in clinic and research?
- neurodegenerative diseases rarely manifest overt signs and symptoms until long after neurodegeneration has began.
-> so early treatment is impossible without early diagnosis
-> therapeutic challenge is considerable
for CNS disorders , studies of affected tissue is very difficult until death.
