Neurodegenerative Diseases Flashcards
Define neurodegeneration?
Progressive loss of neurons
Define neurodegenerative disease?
Disease caused by neurodegeneration
When does neurodegeration start?
Any stage of life but most common ones are associated with ageing, rare ones start in childhood/from birth.
What is the cause of earlier onset of neurodegenarative disease?
greater genetic contribution - likely monogenic mutation
What is the cause of later onset of neurodegenarative disease?
sporadic / idiopathic disease
Give an example of a nuerodegenerative disease from birth?
Spinal muscular atrophy (SMA)
What parts of the nervous system do neurodegenerative diseases affect?
CNS/PNS sometimes both
Are neurodegenerative diseases similair to each other?
no they are highly HETEROGENEOUS (vary alot)
in cases they are INHERENTLY PLEIOTROPIC, in other cases conditions may overlap phenotypes but have very diff genetic causes (diff mutations for one disease)
Define pleiotropic?
Symptoms manifest differently in different people
What is the common pattern (order) in neurodegenerative disease?
1) Molecular impairment in cell
2) decreased transmission at synapse
3) dying back of neurites (axons/dendrites)
4) cell death
What is a neuron’s achilles heel?
Distance between axon terminal and nucleus (longer axons = longer transport = more dangerous)
What is the myelin sheath made of in CNS vs PNS?
CNS - oligodendrocytes
PNS - schwann cells
What are common features seen in neurodegenerative disease (from molecular level)?
protein aggregation (proteinopathies) Lysosomal dysfunction (resulting in degredation) Mitochondrial dysfunction Associated inflammation via activation of glia
Why is neurodegenerative disease incurable?
Signs don’t show until long after neurodegeneration started so early treatment not possible without early diagnosis. After diagnosis, too much damage already done
If CNS affected, hard to study affected tissue - can not identify problem until after death in brain pathology
What is the most common neurodegenerative disease?
dementia
What is the causal/correlation relationship of age with dementia?
onset of dementia usually in higher age, but dementia not normal part of ageing!
What is dementia?
Fast and sudden decline in memory and other cognitive functions that impair quality of life - distinct from normal ageing symptoms
What cognitive lapse happens in normal ageing?
GRADUAL decline in normal cognition and gradual changes in personality
What are the 3 pathological hallmarks of dementia?
Brain shrinkage (+enlarged ventricles) causing lack of ability to form memories Proteinopathies
What are the 2 types of proteinopathies in dementia?
Amyloid plaques and neurofibrillary tangles
What are amyloid plaues?
EXTRACELLULAR protein aggregates
enriched in alpha beta peptides
What are neurofibrillary tangles?
INTRACELLULAR protein aggregates
- enriched in Tau protein
What is another name for neurofibrillary tangles?
paired helical filaments
How are amyloid plaques formed step by step?
AB fragment on a transmembrane protein called amyloid beta precursor protein (APP)
Beta secretase cleaves a peptide from transmembrane protein exposing AB peptide
gamma secretase cleaves AB peptide released it intro extracellular space when it accumulates forming extracellular amyloid plaque (proteinopathy)
What are the pathological hallmarks of AD?
proteinopathies
What is the amyloid hypothesis?
Mutations to 3 proteins involved in AB peptide process cause rare early onset of ALZHEIMERS - amyloid plaque cause of alzheimer’s disease
What are the 3 proteins that are mutated in the formation of amyloid plaques in alzheimer’s disease?
APP (transmembrane protein itself)
PSEN1 and PSEN2 (presenilin-1 and presenilin-2 both a component of gamma secretase)
What does Tau normally do?
Binds to microtubules on axons
What happens to Tau pathologically?
Tau becomes hyperphosphorylated causing it to become displaced which goes onto aggregate forming tangles + also destabilises microtubules.
What are the roles of microtubules in post-mitotic cells?
Structure/shape of cell
Positioning of organelles
Motorway for transporting vesicularcargo
How does the loss of microtubules due to Tau aggregation (neurofibrillary tangles) cause in Alzheimers?
No more microtubules = no more motorway for transporting vesicular cargo = problem on longer axons - links back to achilles heel
What is the Tau hypothesis?
Seen before amyloid plaques (suggests they come first) suggesting Tau is upstream of AB
Tau increases from early through to late stages - correlates cell death with progression of alzheimers
When do neurofibrillary tangles form in AD?
Late onset so not genetic cause
Does amyloid hypothesis or tau hypothesis cause alzheimers disease?
More evidence for amyloid but may not be a cause (inhibitting AB aggregation shows not difference)
Which form of AB and tau is more pathogenic?
Oligomeric forms
What are risk factors of AD (alzheimers disease?
Down syndrome (APP gene is on chromosome 21)
Gender (more in women)
High BP, cardiovascular disease, diabetes
Low education (low cognitive reserve)
head injury (trauma)
smoking and drinking
ONLY SMALL GENETIC RISK CONTRIBUTION FOR LATE ONSET AD
What are the motor symptoms of parkinson’s disease?
1) resting tremor
2) bradykinesia (slow movement)
3) rigidity
4) postural instability (fall over)
What are the non motor symptoms of PD?
Depression and anxiety
Loss of smell
Sleep disorders
Constipation
Dementia
Other psychiatric conditions
What are the pathological hallmarks of PD?
LOSS OF DOPAMINERGIC NEURONS OF SUBSTANTIA NIAGRA
proteinopathy - lewy bodies
What is the substantia niagra? and how does it look in PD?
Part of basal ganglia in midbrain - usually dark due to dopaminergic neurons - lost in PD = lack of pigmentation (normally should be dark)
Which parts of the brain does PD affect?
Not only substantia niagra - dopaminergic neurones lost in other regions too
What are lewy bodies?
INTRACELLULAR PROTEIN AGGREGATES
enriched in alpha synuclein protein (cyclical protein inside cell nucleus)
What effect does Lewy bodies have on PD?
Not pathogenic unlike amyloid and tau in AD and dementia
What are the 3 clear genetic causes of familial PD?
1) Early onset due to recessive mitochondrial conditions
2) Later onset (sporadic) due to automsomal dominant PD
3) mutations that cause PD-plus conditions
