Neurological Disease- Alzheimers Flashcards
What is dementia?
It is defined as a progressive deterioration in cognitive function
Begins with a short term memory loss
Evolves to profound cognitive impairments
Memory loss persists and worsens (long term)
What are the clinical symptoms of Alzheimer’s disease?
In AD there is a rapid cognitive decline
Most common cause of dementia
Clinical symptoms:
- Memory loss
- Abnormal behavior (personality- aggression, depression)
What is the main risk factor for AD?
Age, as life expectancy increases, AD is becoming more prevalent
What is the incidence of AD?
Incidence doubles every 5 years:
- 1% at 60 years, 2% at 65
- 8% at 75 years, 16% at 80 years
>50,000 people in the UK have AD
What are the pathological hallmarks of AD?
- Amyloid plaques
- Extracellular deposits of Beta Amyloid protein
- Intracellular Neurofibrillary tangles (NFT)
- Hyperphosphorylated tau protein
Leads to neuronal loss
How is pathogenesis of AD described?
Lack of knowledge regarding AD etiology
Unknown cause
Some familial cases (10%)
Several hypotheses exist
What hypotheses exist to explain AD?
- Amyloid cascade hypothesis
- Tau and tangle hypothesis
- Mitochondrial dysfunction/oxidative stress hypothesis
- Cholinergic hypothesis
What is APP?
Amyloid precursor protein (APP) is a transmembrane protein
Large extracellular domains
Produced in large quantities in neurons
Function unknown
What do Amyloid plaques go through?
Undergoes post-translational processing
APP proteolysis
Broken down into different fragments
Abnormal processing of APP in AD
How are APP’s processed?
APP is cleaved via the sequential action of secretases
Different protein fragments formed
3 secretases involved in cleavage of APP:
- Alpha
- Beta
- Gamma
What do secretases do?
Secretases can produce non-pathogenic and pathogenic products
Protein fragments formed depends on which secretases are active
Neurotoxic amyloid beta protein formed in AD dye to abnormal APP processing
How does the non-amyloidogenic pathway work in APP processing?
Under normal circumstances a and y secretases cleave APP
alpha secretase cleaves APP to produce:
- Soluble APPa (sAPPa) which is released into the extracellular domain
Membrane associated C terminal fragment
Y secretase then cleaves this fragment to produce P3 and AICD
Both of which are important to cell signalling
How does the amyloid pathway work in AD?
In AD, the amyloid pathway:
APP is cleaved by beta secretase
Releases sAPPB
The membrane associated C terminal fragment remains in the membrane
Y secretase then cleaves this fragment to form Beta amyloid peptide and AICD
Why is the produced Beta amyloid peptide important?
It can be degraded (cleared) by proteases
In AD increased formation and defective clearance of this peptide results in an accumulation of the protein
It aggregates in the extracellular space forming plaques
Beta amyloid peptide is neurotoxic
How is the amyloid cascade hypothesis described?
Mutations in the genes encoding APP or secretases cause familial AD
Inherited and early onset AD
Favours generation of Beta amyloid peptide
What are the NFT’s?
Neurofibrillary tangles (NFT’s) are formed from intracellular aggregates of the tau protein
Tau is a microtubule associated protein (MAP)
What do microtubules contribute to
Microtubules (cytoskeleton) contribute to a number of cell processes e.g.
Intracellular trafficking
Cell morphology
Maintenance of cell shape
What is the Tau protein?
Tau is a microtubule associated protein (MAP)
Tau promotes microtubule assembly
Tau maintains microtubule stability
What is binding of Tau to microtubules regulated by?
By it’s phosphorylation state
Kinases and phosphatases (enzymes) control protein phosphorylation
Phosphorylation is necessary for biological activity but must be tightly regulated
How is regulation of phosphorylation impacted in AD?
In AD hyperphosphorylation of tau decreases its binding to microtubules
Causes conformational changes and misfoldings in protein structure
Loss of tau binding to microtubule
What happens to the tau protein in AD?
Tau aggregates inside neurons
Accumulation of fibrillary structures (NFTs)
Disrupts microtubule organisation
Prevents microtubule assembly
Contributes to neurotoxicity
What is Ach?
Acetylcholine is a neurotransmitter
Has a role in learning and memory
Loss of neurons in specific anatomical regions which control cognitive functions in AD
Cholinergic hypothesis of AD
In AD, how is cholinergic transmission affected?
There is a reduction in cholinergic transmission due to a:
- Deficit in the enzyme responsible for Ach synthesis- Choline acetyltransferase (ChAt)
- Reduction in Ach release following neuron depolarisation
- Reduction in Ach reuptake
- Loss of cholinergic neurons in the brain
How does mitochondrial dysfunction relate to AD?
Mitochondrial dysfunction increases with age
- Compromised ATP production
- Oxidative stress
Hypothesised that age related mitochondrial dysfunction is accelerated in AD
Contributes to neuronal death
How is AD currently diagnosed?
Need earlier diagnosis as currently only confirmed at post-mortem
No cure drugs only improve symptoms
What is the problem with drugs for AD?
Timing of drug administration is likely to be an issue
Drugs are administered at late stage where protein deposits have been developing over decades
Irreversible damage done prior to any symptoms emerging
What is needed to treat AD?
Need novel therapeutic strategies and earlier diagnosis
Requires better understanding of pathogenesis
What are the 2 main drugs used to treat AD?
Cholinesterase inhibitors:
- Donepezil
- Rivastigmine
- Galantamine
-NMDA receptor antagonists
- Memantine
What do acetylcholinesterase inhibitors do?
- Prevent breakdown of ACh
- Increase concentration of ACh
- Increase communication between neurons that use ACh
Where does the pathology of AD extend to in later stages of AD?
To the glutamatergic system
Glutamate is a neurotransmitter that is released in excessive amounts from damaged neurons in AD
It can cause further damage
Evidence that glutamate receptor activation can promote Beta amyloid peptide synthesis
What do NMDA receptor inhibitors do?
NMDA (Glutamate) receptor inhibitors block the activity of glutamate to protect against its detrimental effects
