Week 8.1 AD Flashcards
Who discovered AD? and when?
What did the autopsy of his patient reveal?
Alois Alzheimer first reported Alzheimer’s disease (AD) in 1906
Autopsy of patients revealed:
Cellular debris around nerves
–Senile plaques
Bundles of tangled nerves
–Neurofibrillary Tangles
What is AD?
Is it infectious?
…it is the most common form of _____?
Why is AD becoming an increasning problem?
•Alzheimer’s disease (AD) is a Neuro-degenerative disorder that progressively destroys brain cells.
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•It is non-infectious, but is the single most common cause of dementia.
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- In the UK up to 820,000 people suffering from Alzheimer’s disease, 35 million world wide.
- With an ever-ageing population Alzheimer’s is the fourth most common cause of death in the western world, after heart disease, cancer, and strokes.
What are the symptoms of AD?
Diagnosis?
•Forgetfulness (Also a feature of normal ageing)
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•Severe memory loss
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•Dysphasia (inability to find the right word)
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•Loss of numerical abilities
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•Anxiety and mood changes
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•Psychosis, hallucinations and delusions
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•Aggressiveness or docility
**The only full-proof diagnosis is via a post mortem **
What is the Brain Pathology of AD?
What are AD sufferes characterised by?
Where do the plaques collect?
What are the main constituent of the amyloid plaques?
What is the second characteristic of AD, where is it found, what is it called?
- Alzheimer’s (AD) is characterised by innumerable deposits of extracellular amyloid plaques.
- The plaques collect in the cortical interstitium and cerebro-vasculature.
- The main constituent of these amyloids is a small peptide; amyloid-b-peptide (Ab).
- Ab plays a critical role in the initial build up of amyloid plaques.•Progression of Alzheimer’s disease (AD) is also characterised by intracellular neurofibrillary tangles, which consist of paired helical filaments containing hyper-phosphorylated tau protein
What is found in the extracellular plaques?
What is found in the intra-cellular neurofibrillary tangles?
Extra-cellular Plaques of Amyloid beta
Intra-cellular neurofibrillary tangles of tau
What are the risk factors for AD?
Do most cases have a family history? What about early onset AD, what percentage does early onset make up?
What does AD have similartis too?
Race, culture, environment, lifestyle has little if any effect as risk a factor to AD.
•Most cases of AD have no family history. However, early onset AD (aged 30- 65) (5% of cases) can cluster in families
•AD might be linked to a severe blow to the head. Punch-drunk syndrome has similarities with AD
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What reduces the risk of AD?
Is there a cure?
What treatments are there?
- Intellectual activity might reduce risk
- Low cholesterol diet – because high cholesterol dietincreases pathology in animal models
- Present Treatment
- No known cure
- Drugs that inhibit the enzyme acetyl-cholinesterase and raise acetylcholine levels, give benefits for a few months
Amyloid-b-peptide:
Where are the amyloid fibrils found?
What are the amyloid fibrils composed of?
When were they detected?
What are the major forms of Ab?
•The amyloid fibrils found in senile plaques, found extra-cellularly, are principally composed of amyloid-b-peptide (Ab).
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•Not detected until 1984
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•Amyloid-b-peptide can be between 39 and 43 residues in length, Ab(1-40) and Ab(1-42) are the most abundant.
Which form of Ab protein is more insolube? it can be described as the more _____ form
Ab is ______ the shorter Ab is more _____ and _______ slowly
What protein is Ab derived from?
•Ab(1-42) rapidly forms insoluble aggregates and is the more amyloidogenic form
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•Ab is neuro-toxic the shorter beta-amyloid peptide is more soluble and aggregates slowly.
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•Ab is derived by the proteolysis (clevage) of the transmembrane protein, amyloid precursor protein (APP).
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•The putative transmembrane region, residues 28-42 of Ab, are rich in hydrophobic residues. The p3 peptide is also found in amyloidogenic material and is derived from APP. This peptide contains residues 17-42 of the Ab peptide.
Where is soulube Ab40 and Ab42 found?
•Soluble Ab40 and Ab42 is found in the cerebrospinal fluid (CSF) and plasma of all humans.
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•Ab40 has a concentration of 1 nano-Molar in CSF.•Critically still unanswered questions are the reasons/trigger for the amyloid formation of these peptides
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•Ab is neuro-toxic. However the site, mode of action and form of Ab is not clear
Production of Ab from
Amyloid Precursor
Protein (APP)
What is APP?
What are the amino acid lengths of the 3 major isoforms of APP?
- Ab is derived from APP
- APP is a trans-membrane glyco-protein.
- There are three major isoforms of APP: 695; 751 and 770, amino acids in length.
- The putative transmembrane spanning residues are 700-723.
Processing of APP:
What enzymes are used, which are for Ab production, and p3?
What is the pathway of Ab production from APP?
Beta-secretase and Gamma-Secretase (Ab)
Alpha-secretase and Gamma-Secretase for p3
- The APP is protruding through the neuron’s membrane
- B-secretase cleaves APP at one end of the beta-amyloid peptide
- Then G-secretase cleaves the APP at the other end
- Single beta-amyloid peptids clump into soluble oligomers - eventually this dumping leads to plaques
APP is subject to a series of post translational processing events
What PTM result in the production of p3 peptide?
What is the alternative pathway - resulting ing Ab?
•At the cell surface some APP molecules undergo proteolysis via the a-secretase pathway releasing a large soluble domain a-APP(18-687). The membrane-retained fragment is further processed by g-secretase to produce the amyloidgenic peptide p3.
Processing of APP
is done by the enzymes;
B-Secretase
- What does it cause? at what residues?
- G-Secretase
- is a mutli protein complex that includes ____
- what ratio does it determine?
- mutations of the ___ has been linked to causes of _______ AD
b-Secretase (BACE)
- Causes cleavage at residue 671 (N-term of Ab)
- Structure determined in 2000, resemblance to aspartyl proteases, hydrolysis via Asp93 and Asp289
g-Secretase (Multi-protein complex includes presenilins)
•Unusual because clips APP in middle of transmembrane -hydrolysis in a water free environment
•Important as determines ratio of Ab40 to Ab42
• g-Secretase is a multi-protein complex contain presenilin-1 and -2 (PS1 and PS2)
As many as 100 different mutations of the presenilins have been identified to cause familial Alzheimer’s
Processing of APP to Ab
is dependent on secretases
Where are gamme-secretases found?
Where are most Ab generated?
Secretase’s are membrane associated
g-secretase has been found in the ER, golgi, endosomes and plasma membrane
Most Ab is generated in the TGN and endosomes in cholesterol rich membrane rafts
In neurons it is thought that APP is trafficked down the axon where Ab generated with in vesicles and then released at the synapse
Ab is cleaved into the lumen of vesicles which travel down the axon are then released at the synapse to form plaques
Progression of AD:
APP
Normal Function and structure
What happens to productio of Ab when there is a dysfunction of APP?
Brain trauma causes up regulation of APP, what is AD similar too?
What are the two approaches to understand function of APP?
A Function for APP?
Dysfunction of APP could lead to up regulation of APP causing over production of Ab-
Brain trauma causes up regulation of APP. AD has similarities to punch drunk syndrome
Two approaches to understand function
1) Use knockout mice
2) Determine structure to suggest function
