Neurodegenerative disease Flashcards
What is neurodegeneration?
The progressive loss of neurones (CNS, PNS or both)
Neurodegenerative diseases are highly heterogeneous
Some disease names are really umbrella terms:
> conditions with overlapping phenotypes but different causes
Some diseases are inherently pleiotropic
> symptoms manifest differently in different people
Common features in the process of a neurodegenerative disease
Many follow a similar pattern: > molecular impairment somewhere in the cell > Decreased transmission at synapse > "Dying back" of neurites > Cell death
Common features involved in neurodegenerative disease?
Frequently involve: > Protein aggregation > Lysosomal dysfunction > mitochondrial dysfunction > associated inflammation via activation of glia
Challenges of treating a neurodegenerative disease
They rarely manifest overt signs and symptoms until long after neurodegeneration has begun
> early treatment s impossible without 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 understand the causes
They remain incurable
What is dementia
A decline in memory and other cognitive functions that impair a person’s quality of life
How does dementia differ from normal loss of memory
What are pathological hallmarks of Alzheimer’s disease
Brain shrinkage
Proteinopathies
>Amyloid plaques
-Extracellular Protein aggregates
-Enriched in Aβ peptides
> Neurofibrillary tangles
- also called paired helical filaments
- intracellular protein aggregates
- Enriched in Tau protein
What are Aβ peptides
Aβ peptide is cleaved from a transmembrane protein called amyloid beta precursor protein
What is the Amyloid hypothesis?
Mutations to three proteins involved in Aβ peptide processing are known to cause rare early onset forms of Alzheimer’s:
- APP
- PSEN1 and PSEN2 (Presenilin-1 and Presenilin-2; both a components of γ-secretase)
What are Tau and neurofibrillary tangles?
- Tau normally binds microtubules in axons
-Hyperphosphorylated Tau is displaced causing:
> Tangles
> Destabilised microtubules
Why are microtubules important in neurites?
The 3 main roles of microtubules are:
- Structure/shape
- Positioning of organelles
- Motorways for transporting vesicular cargo
What is a neurones achilles heel?
Distance between axon terminal and nucleus
What is the Tau Hypothesis?
neurofibrillary tangles are:
- Seen before amyloid plaques
- well correlated with cell death and progression
suggests Tau is upstream Aβ = Tau hypothesis
Which hypothesis is the right one?
Probably more evidence for amyloid, but…
- Therapies based on inhibiting Aβ aggregation so far haven’t worked
Tangles and plaques may be red herrings
- Are they pathogenic or by-standers? Or even protective?
- Oligomeric forms of Aβ and tau are more likely to be pathogenic
Could both be downstream of other factors?
What are of pathological hallmarks of PD?
Loss of dopaminergic neurones of the substantia nigra (basal ganglia in the midbrain)
*other brain regions are also affected
Proteinopathy
-Lewy bodies
>Intracellular protein aggregates
> Enriched in α-synuclein protein (involved in neurotransmitter release)
Lewy bodies not pathogenic, but ↑ α-synuclein is
How is GBA linked to α-synuclein
GBA encodes GCase (β-glucocerebrosidase ),a lysosomal enzyme
α-synuclein is degraded in the lysosome
They are connected…
Describe the cyclical process of Neuroninflammation
Positive feedback cycle
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?
