Lecture 20 - Alzheimer's Disease - Molecular Pathogenesis Flashcards
Describe the ‘discovery’ of Alzheimer’s disease
What are the two key pathological features that were observed?
1906: German neuropathologist Alzheimer
• He documented the first case:
• Person called Auguste D
Examination of Auguste D’s brain post-mortem revealed:
• Globs of sticky protein between Neurons: Amyloid
• Bundles of fibrils within neurons: Neurofibrillary tangles
Is AD a normal part of ageing?
No, it is a distinct disease
Describe the features of Amyloid plaques
What is amyloid?
Amyloid is a starch-like material
Composed of:
• Aggregated Amyloid-β peptide
• Other components as well:
• Metal ions
• Beta-pleated sheet structures (protofibrils) form fibrils, then form plaques
- Rapidly turned over in the brain
- Associated w/ secondary inflammation
What still remains a mystery in AD?
Why amyloid aggregates & induces neuronal damage only late in life
How many people in Australia w/ AD?
Half a million
This is predicted to increase in coming year
• Economic, social & public health burden
Describe the general neuropathology in AD
- Gross atrophy
- Extracellular neuritic (amyloid) plaques
- Intraneuronal neurofibrillary tangles
- Cerebrovascular amyloid angiopathy
- Activation of microglia & hypertrophy of astrocytes
- Dementia / memory impairment
- Loss of neurons
What is the role of microglia in the brain?
Describe their role in AD
Resident macrophages in the brain
In AD they are:
• Overactive
• Inflammatory response
What is the name for the loss of memory that occurs w/ dementia?
What is responsible for this memory loss?
Amnestic dementia
• More about loss of synapses, rather than loss of neurons
Describe what is thought to be the underlying factor in memory loss in early & late dementia
Early dementia: loss of synapses
Late dementia: loss of the neurons themselves
Describe gross brain atrophy in AD
As the disease progresses, there is loss of neurons, leading to gradual shrinkage of the brain
In severe AD (takes years to get to this stage) the brain is extremely small compared to a normal brain
Compare location of the amyloid plaques & neurofibrillary tangles
Amyloid plaques:
• extracellular; throughout the grey matter
• i.e. in brain parenchyma
• Also within the vasculature of the brain
Neurofibrillary:
• Intracellular (within the neurons)
Describe Green-red bifringence
What is this used for?
Identification of ‘Amyloidogenic’ structures
Congo red stain, then amyloid:
• Appear red in normal light
• Appear green in polarised light
Indicates presence of beta pleated sheet structure within the plaque
Describe how protofibrils can form, what they are, and what the significance of this is
A protofibril is this beta-sheet structure
Under certain environmental conditions the protein structure can partially unfold and form beta pleated sheets
Protofibrils mature into fibrils, then plaques
Summary:
- Partially folded protein monomer (A-B peptide)
- Association of these monomers into protofibrils
- Fibrils
- Plaques
What are the oligomers?
Describe their importance in AD
Many of the subunits:
• the Aβ peptide
coming together to form a larger structure
Can become cross linked:
• di-tyrosine cross link
increasing the stability of the oligomer
They are through to be the primary toxic form of Aβ
• Monomers not harmful
• Amyloid fibrils possible just the end point, and not harmful in and of themselves
Describe the generation of Aβ
- Hydrophobic
- Sits in membranes of cells
- Cleaved from a larger precursor protein by ‘secretases’
- Cleavage occurs at the membrane
- Released into the extracellular space
- NB can be recycled back into the cell by endocytosis
- Deposited between cells
How long is the Aβ peptide?
40-42 aa
Depends on disease state
What are secretases?
These are proteases
These cleave the Aβ peptide from larger Amyloid precursor proteins
What is APP?
Describe features & function
Amyloid precursor protein
- Integral membrane protein concentrated at synaptic connections
- Gene located on chromosome 21 → implication for people w/ Downs syndrome
- Many different domains
- Many post-translational processing
Function: • Unknown, but many activities associated: - growth promotion - regulation of synaptic function - metal homeostasis - cell signalling
Describe the cleavage of Aβ from APP
What happens to APP after cleavage?
- Beta-secretase (BACE) cleaves beta site on the protein
- Gamma-secretase cleaves gamma site on the protein
- Aβ released from APP
APP released as soluble form
What is alpha-secretase?
Another secretes that can cleave APP
If this happens, Aβ is prevented from forming