neurodegenerative diseases Flashcards
define neurodegeneration
neuro and progressive loss
basic detail
affect the CNS or PNS
begin at any stage of life
most common are associated with ageing
rarer types of neurodegenerative diseases start in childhood or even from birth
earlier age of onset = greater genetic contribution
later age of onset = more likely a sporadic disease
common features
many follow similar pattern:
- molecular impairment somewhere in cell
- decreased transmission at synapse
- cell death
common features 2
protein aggregation
lysosomal dysfunction
mitochondrial dysfunction
associated inflammation via activation of glia
clinical and research conundrums
neurodegenerative disease rarely manifest overt signs and symptoms until long after neurodegeneration has begun
early treatment is impossible without early diagnosis
therapeutic challenge is considerable
for CNS disorders, studies of affected tissue is very difficult until death
advanced brain pathology is of little help to understanding the causes
neurodegenerative diseases remain incurable
alzheimers introduction.
the most common neurodegerative disease and most common cause of dementia
onset is usually >65 years of age, but 10% are early onset, starting 30s onwards
10% people aged 65+
50% people aged 85+
AD is not a normal part of ageing- it is a disease
dementia
decline in memory and other cognitive functions that impair quality of life
impairments in dementia are distinct from normal cognitive lapses
history of Alzheimer
First described by Alois Alzheimer, a German psychiatrist and neuroanatomist, in 1906/7
Initial psychiatric and pathological observations made in younger patients
“Pre-senile dementia”
Pathology then found to be widespread in older patients
pathological hallmarks 2
proteinopathies:
amyloid plaques
- extracellular protein aggregates
- enriched in AB peptides
neurofibrillary tangles
- also called paired helical filaments
- intracellular protein aggregates
- enriched in Tau protein
AB and APP
AB peptide is cleaved from a transmembrane protein called amyloid beta precursor protein by proteases
amyloid hypothesis
mutations to three proteins involved in AB peptide processing are known to cause rare early onset form of Alzheimers
APP
PSEN1
PSEN2
since early 1990s amyloid hypothesis of AD which states AB and or amyloid plaques are cause of AD
TAU and neurofibrillary tangles
tau normally binds microtubules in axons
hyperphosphorylated tau is displaced causing:
- tangles
- destabilised microtubules
importance of microtubules in neurites
in all post mitotic cells, microtubules have 3 main roles:
- structure/shape of cell
- positioning of organelles
- motorways for transporting vesicular cargo
tau hypothesis
in typical late onset AD
neurofibrillary tangles are:
- seen before amyloid plaques
- well correlated with cell death and progression
-suggests Tau is upstream AB = tau hypothesis
tau or amyloid
still really controversial
probably more evidence for amyloid, but therapies based on inhibiting AB aggregation so far haven’t worked
tangles and plaques may be red herrings
- oligomeric forms of AB and tau are more likely to be pathogenic
other risk factors
Down syndrome
gender
high BP, cardiovascular disease, diabetes
low education
head injury
smoking and drinking
only small genetic risk contribution for late-onset AD
parkinsons introduction
second most common neurodegenerative disease
onset usually 60-65 years of age, 10% start before 45 years of age
lifetime risk:
- male = 2%
- female = 1.3%
like AD, Parkinson’s is incurable
symptoms of Parkinson’s
movement disorder, with four cardinal features
- resting tremor
- bradykinesia
- rigidity
- postural instability
non-motor symptoms
- 90% of patients display additional non-motor symptoms
including:
- depression
- loss of smell
- sleep disorders
- constipation
- dementia
- other psychiatric complications
pathological hallmarks 1
loss of dopaminergic neurons of substantial nigra
- neurons that produce the neurotransmitter dopamine
- part of basal ganglia in midbrain substatia nigra = dark substance
normal brain section:
- neurons visible by eye due to expression of neuromelanin
PD brain section = lack of pigmentation shows loss substantially nigra
pathological hallmarks 1
histology of dopaminergic neurone loss
pathological hallmarks 2
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
familial PD
10% of cases have clear genetic cause
three rough categories:
- early/juvenille onset recessive mitochondrial conditions
- late/later onset autosomal dominant PD
- mutations that cause PD plus conditions
early onset mitochondrial PD
mitochondria have finite lifespan due to oxidative stress
damaged mitochondria are selectively removed from 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 is PD distinct from late-onset sporadic PD
late onset genetic PD
- some genetic causes found from kindred studies, but more limited:
- SNCA gene amplification
- LRRK2 gain of function
- VPS35 gain of function
- GBA loss of function
GBA and a-synuclein
GBA encodes GCcase B glucocerebrosidase
a-synucelin is degraded in the lysosome
they are connected
PD and lysosomes
other PD genes play roles in processes involving lysosomes
consistently, autophagy is dysregulated in PD brains
problems in autophagy will also lead to mitochondrial dysfunction
endocytic pathways are big focus in PD research
GWAS of sporadic PD
risk genes:
- has shown many cause genes influence risk
- found many new PD genes
- now believed as much as 30% of PD risk is genetic
Tau and PD
linkage of MAPT to PD was a big surprise
neurofibrillary tangles can be found in PD brain, but not to any great extent
however,
more NFTs in brains of LRRK2 PD
microtubule disruption long implicated in PD
other risk factors
gender red hair head injury not smoking, not consuming caffeine herbicides, pesticides, insecticides exposure to metals general anaesthesia
neuroinflammation
activation of the immune system within the nervous system
in brain, typically means activation of microglia
ageing and microglia
reactive microglia can be protective of neurons or damaging
protective = anti-inflammatory, normal removal of unhealthy cells
damaging;
= pro inflammatory, response to pathogens
ageing induces shift towards production of damaging reactive microglia, due to changes in microglial gene of expression
neuroinflammation in neurodegeneration
external trigger = AB, environmental toxins, pathogens
microglial activators= a-synuclein and other proteins
neurotoxic insult = injury, toxins, gene, mutations
neuronal damage/death
neuroinflammation as a cause
Many Alzheimer’s risk factors cause raised levels of circulating inflammatory cytokines
High BP, Cardiovascular disease, Diabetes, Smoking
In principal, effects can cross the blood-brain barrier
Enough to cause AD? Not known
But an interesting story emerging in PD…
PD gut-to-brain
Lewy body pathology in gut often precedes pathology in brain
Evidence that gut inflammation is sufficient to cause gut Lewy bodies
Spread to brain via vagus nerve?
Role for microbiota?
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?!
