Neurodegeneration Flashcards
What is neural loss?
- Type of cell death
- neuronal loss = hallmark of
- neurodegeneration
- Necrosis and apoptosis
What is necrosis ?
Tissue death resulting from damage, ischaemia or disease
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Cellular & mitochondrial swelling &
loss of membrane integrity
Does not require energy
Influx of sodium & calcium ions
Eventual rupture of cell
Internal components discharged into
extracellular space - leads to
inflammatory response and reactive
gliosis (activation of glial cells)
Dead tissue phagocytosed by
microglia
Thought to be an unregulated
process, but evidence mounting to
suggest it may be regulated by
signalling pathways
What is apoptosis?
Programmed cell death. Essential for growth and development but also induced by CNS pathologies.
Characterised by cell shrinkage &
condensation of nuclear chromatin
Orchestrated by proteolytic
enzymes called caspases
Caspases dismantle neuronal
cytoskeleton and nuclear DNA in an
organised fashion (requires energy)
Viable mitochondria are packaged
into apoptotic bodies and are
internalised by neighbouring
phagocytes
No inflammatory reaction
What are important functions of apoptosis?
- Most newly formed nerves are primed to commit ‘cellular suicide’
(programmed cell death) unless rescued by trophic factors e.g. dorsal root ganglions are dependent on nerve growth factor (NGF) - During CNS development 50% of neurones are deliberately deleted if they fail to (i) reach their intended targets or (ii) fail to make
appropriate connections with other cells - Apoptosis also important for destroying injured or abnormal cells
e.g. damage to nuclear DNA is a trigger for apoptosis in order to prevent tumours
e.g. used by lymphocytes to sacrifice virus-infected cells
What are the causes of cell death?
Excitotoxicity, Oxidative stress , Nitric oxide
How does excitotoxicity cause cell death?
) Excitotoxicity
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Excessive/prolonged stimulation by excitatory neurotransmitters
(e.g. glutamate) results in cell death. Leads to prolonged depolarisation and excessive intracellular Ca2+.
May lead to activation of harmful calcium dependent enzymes (e.g. phospolipases which impair integrity of cell membranes)
Low grade, chronic excitotoxicity may cause chronic neuronal
damage in some disorders e.g. motor neuron disease and Alzheimer’s disease.
How does oxidative stress lead to cell death?
Produces reactive oxygen
species (free radicals)
Can damage cell membranes,
proteins and DNA
Normally, scavenging mechanisms & molecules deal with free radicals e.g. superoxide dismutase & catalase.
Excess generation of free radicals or reduced capacity of scavenging system leads to oxidative stress
Leads to cell death (cross-linking)
Membrane damage
(lipid peroxidatjon)
Oxidative stress
(cross-linking/breakage)
Reactive oxygen species damage key cellular
components e.g. proteins, cell membrane
and DNA
How does nitric oxide cause cell death?
3) Nitric oxide
Nitric oxide gas is a free radical species
Plays a number of important physiological roles e.g
vasodilator, regulates inflammatory and immune response
* Excessive production of NO is a feature of excitotoxicity
May damage proteins by interacting with cysteine and
tyrosine residues
* Excessive production contributes to cell death in
neurodegenerative diseases, multiple sclerosis and stroke
What is neuronal repair?
- neuronal cells do not regenerate except in olfactory system
- ## Neural stem cells may have therapeutic potential
What are neurodegenerative diseases?
Heterogeneous group of progressive,incurable neurological disorders
that are more common later in life
*Alzheimer’s Disease (AD)
*Amyotrophic Lateral Sclerosis (ALS)
*Dementia with Lewy Bodies (DLB)
*Huntington’s Disease (HD)
*Multiple System Atrophy (MSA)
*Parkinson’s Disease (PD)
*Prion diseases (e.g. Creutzfeldt-Jakob disease)
Linked by a common pathological hallmark: the
presence of abnormal protein accumulations
What are the general features of neurodegenerative diseases?
General features
* Selective loss of specific populations of neurones
* Associated with deposits of abnormal protein
accumulations that may be intra or extra cellular
* Referred to as proteinopathies
* Affected brain region shows neuronal loss — affects
specific neurones and spares others
* Clinical features are determined by the location of
abnormal proteins (rather than the protein involved)
* In most cases it is not clear why specific populations are susceptible (called selective vulnerability)
What is protein misfolding?
Unfolded protein response
Presence of misfolded proteins triggers the unfolded protein
response (UPR)
This upregulates molecular chaperone proteins that attempt to refold abnormally configured proteins
Disposal of abnormal proteins
Abnormal proteins are tagged with ubiquitin
Ubiquitinated proteins are targeted to the proteasome (a large protein complex) that digests protein
In neurodegenerative diseases there is an accumulation of abnormally folded proteins - or a failure of the normal cellular mechanisms for their disposal
What is protein aggregation?
- Abnormal proteins can accumulate inneurones (or glial cells). Called inclusion bodies.
- Often cytoplasmic, but can be nuclear
- Can also accumulate in extracellular component
- Many pathological aggregates have a beta-pleated
sheet structure that can stack together to form
insoluble fibrils - Often referred to as amyloid
- Deposition of amyloid is responsible for many diseases,
but most understood amyloid disease is Alzheimer’s disease
What are the clinical aspects of alzheimer’s?
Memory loss
* Loss of short-term memory is a prominent feature
Recollection of personal experiences (episodic memory) particularly affected
May initially be mistaken as age related forgetfulness
As disease progresses earlier memories are eroded
Visuospatial problems
Get lost in familiar places and forget where they have left items
Reasoning and language
Decline in problem-solving abilities and abstract reasoning— impairs
decision making and judgement
Word-finding difficulties & reduced verbal fluency
Psychiatric
Early — depression & anxiety. Late— apathy.
Frustration/irritability
What is the pathology of alzheimer’s?
Reduced brain weight
Cortical atrophy
Enlarged ventricles
Memory loss reflects severe
pathology in the medial temporal
lobe . Includes entorhinal cortex
and hippocampus. Degeneration
of temporal lobe may also affect
recognition of objects and people.
Damage to parietal and temporal
lobes may interfere with ability to
understand spatial relationships
and spatial navigation
respectively.
