Ach and AD Flashcards
(208 cards)
1
Q
How big is the synaptic cleft in NMJ?
A
30nm
2
Q
What does a NMJ sarcolemma contain in order to increase the surface area?
A
Postjunctional folds to form the motor endplate
3
Q
Where do nAChRs accumulate in the NMJ and how many?
A
- On the top of folds
- 10,000 receptors/micrometer^2
4
Q
Where do Na channals accumulate in the NMJ?
A
In the fold valleys
5
Q
Where is Ach hydrolysed in the NMJ?
A
In the fold valleys by AChE
6
Q
What is the first stage of a NMJ’s development?
A
- Agrin
- Motor axons are normally dispersed along the myotubult and when they encounter agrin it is released into the intracellular matrix
7
Q
What is the second stage of the development of the NMJ?
A
- Agrin binds to lrp4
- This then in turn binds to musk causing clustering of Ach in the postsynaptic membrane which is the first step to the adult architecture
8
Q
What is the third step in the development of a NMJ?
A
- Synapse Fromation and maintenance
- AChR clustering
9
Q
What is the fourth step of the development of a NMJ?
A
- The clustering of AChR causes the muscle endplate to form and AChE
10
Q
What does MuSK stand for?
A
Muscle specific Kinase
11
Q
What does Lrp4 stand for?
A
Low density lipoprotein receptor-related protein 4
12
Q
What is Agrin?
A
A glycoprotein
13
Q
What do Neuromuscular- blocking drugs do?
A
- Block neuromuscular transmission
- Cause paralysis of skeletal muscles
14
Q
Where do NM-blocking drugs act?
A
- Presynaptically (e.g. botulinum toxin)
- Postsynaptically (clinically)
15
Q
When NM-blocking drugs are used clinically what are they often used in conjunction with?
A
Anaesthesia to prevent muscle movement during surgery (only when artificial ventillation is available), but they have no sedative or analgesic effect
16
Q
What are two classes of NM-blocking drugs?
A
- Non-depolarising
- Depolarising
17
Q
How do non-depolarising blocking agents work?
A
Competatively block the binding of ACh to the nAChRs without depolarising the endplate
18
Q
What are two examples of non-deplarising blocking agents?
A
- Tubocurarine (causes hypotension so not an adjunct anymore)
- Rocuronium
19
Q
Which class of NM blocking agent is used clinically?
A
Non-depolarising
20
Q
How to non-depolarising NMB agents absord and excreted and what does this mean for administration?
A
- Poorly absorbed
- Rapidly excreted
- Given via IV
21
Q
What are non-depolarising NMB agents partially reversed by?
A
- Administration of neostigmine (anticholinersterase) post operatively
- But requires the addition of atropine to block unwanted muscarinic effects
22
Q
Where do depolarising NMB agents work?
A
Directly onto the muscle fibre, depolarising the motor end plate
23
Q
What side effects do depolarising NMB agents cause?
A
Transient twitching of the skeletal muslce ‘fasciculation’ before neuromuscular block
24
Q
Why does fasciculation occur when given a depolarising NMB agent?
A
- The agent binds tp the receptor causing depolarisation and opens channels similar to ACh casuing repeative excitation that lasts longer than ACh
- Most likely explained by the resistance of depolarising agents to AChE
- No normal contraction can occur becasue the end plate is already depolarised
25
What is the only depolarising NMB agent that is used clinically?
- Suxamethonium (Succinylcholine)
- Fast onset and offset action due to hydrolysis but high mortality rate (bradycardia and malignant hyperthermia
26
What is the structre of suxamethonium?
Two ACh molecules
27
What is the percentage of mortality due to suxamethonium?
65%
28
What are the effects when suxamethonium is combined with anticholinesterases?
There is prolonged effect becasue these are already ACh-like structures
29
What do muscarinic receptor antagonists do to cognition?
Impair it in humans and animals
Further evidence demonstrated a role of cortical cholinergic input system in attention and memory encoding
30
What are the two major cholinergic connections in the brain?
- Magnocellular basal forebrain cholinergic system
- Brainstem cholinergic system
31
What are the 3 brain areas associated with the magnocellular basal forebrain cholinergic system and where do they project to?
- Medial septal nucleus (MS)- basal ganglia
- Diagonal band of Broca (DB)- Neocortex, amygdala, olfactory bulb, basal ganglia
- Nucleus basalis magnocellularis/meynert (nBM)- Neocortex, Amygdala, olfactory bulb
32
What are the two areas that are associated with the brainstem cholinergic system and where do they project to?
- Laterodorsal pontine tegmentun (LDT)- Thalamus, basal ganglia
- Pedunculopontine tegmental nucleus (PPT)- basal forebrain cholinergi system, thalamus, basal ganglia
33
Where are 4 areas that ACh has an important role?
- WM
- Attention (nicotine is a selective cholinergic agonist which facilitated attentional function)
- Episodic memory (improved performance in memory tasks when given nicotine and neuropysiological studies show LTP)
- Spatial memory (have challanged this result so not quite clear yet)
34
Where is acetylcholinesterase (AChE) expressed?
In cholinergic neurons and NMJ (high affinity for ACh)
35
Wich binding site on AChE is important in AD?
Peripheral anionic site (PAS)
Interaction of alpha beta and PAS contributes to the formation of amyloid plaques
36
Where is Butyrylcholinesterase (BuChE) expressed?
- In the hippocampus and temporal neocortex but at lower levels than AChE
- Mainly present in endothelia, glia and neuronal cells with low affinity for ACh
37
What does BuChE associate with to cause AD?
- alpha beta protein and may delay onset and rate of neurotoxic alpha beta fibril formation
- In AD, there is a progressive increase of BuAChE:AChE ratio associated with amyloid plaques and NFTs, and with gradual loss of cognitive function
38
What are 5 FDA approved drugs for AD?
- Tacrine
- Rivastigmine
- Donepezil
- Galamtamine
- Memantine
39
What is Tacrine?
- Competative AChE inhibitor and mAchR modulator
- High side effects related to hepatotoxicity made it be withdrawn from the market
40
Wha is rivastigmine?
- Non-selective pseudoreversible ChE inhibitor
- Enhanced benefits over AChE alone
- Binds to AChE forming a complex and stops the hydrolysis of ACh for hours
41
What is Donepezil?
- Reversible non-competitive ChE inhibitor
- Most widely prescribed drug
- Highly selective for AChE, eliminated cognitive and functional decline
42
What is galantamine?
- Has a dual mechanism of function
- Reversible selective competative AChE inhibitor and nAChRs modulator
- NMDAR potentiation
- Cholinergic and glutamatergic effect
43
What is memantine?
- NMDAR antagonist
- Neuroprotective against alpha beta toxicity, tau phosphorylation, neuroinflammation and oxidative stress
- Appears harmless and well tolerated
44
What effects do alpha4beta2 and alpha7 nAChR agonists have?
- Cognitive
- Sensory processing
- Synaptic plasticity
- Involved in AD pathology- positive effects in trials
45
What is the only alpha4beta2 nAChR agonist to make it to phase 3?
EVP-6124 but failed to produce positive results
46
What is ACh's make up?
Is an ester of acetic acid and choline that functions as a neurotransmitter
47
Where is ACh used?
- Neuromuscular junction (paralysis, convulsions)
- Autonomic nervous system (parasympathetic nervous system)
- Central nervous system (arousal, attention, motivation, memory)
48
Who discovered ACh?
- Otto Loewi confirmed as a neurotransmitter labelling it Vagus stoff
- Was the first neurotransmitter to be discovered
49
How did Otto Loewi discover ACh?
- Stimulated frog's vagus nerve and found that the heart rate slowed and strength of contraction decreased
- Collected all the liquid as a result of stimulating the nerve over and over
- Added to a dish with a different frog's heart
- This new heart started slowing down and the strength of contraction further decreased when put with the liquid
50
What did Henry Dale demonstrate after Otto Loewi?
Ach is released when the motor nerve is stimulated, activating voluntary, striated muscle
51
How did Dale come to his revelation?
Had preparations of leech muscles and applied ACh to see them contract
52
What are 4 functions of ACh?
- Chemical synaptic transmission at NMJ of humans, mammals and some invertebrates
- Chemical synaptic transmission in the human, mammalian and invertebrate brains
- Chemical transmission in the human and mammalian autonomic nervous system
- Non-neuronal signalling roles (skin, bone, immune cells) (not well described, so not much known about this one)
53
What is function of the ACh dependent on?
Its location within the body
54
What are 5 different locations of ACh?
- CNS
- NMJ- somatic efferent system (skeletal muscle)
- Blood vessels, sweat glands, adrenal medulla and sweat glands- sympathetic system
- Galnglia- parasympathetic system (salivary glands)
- Enteric nervous system (controls the gastrointestinal function)
55
What is ACh made up of?
Choline and Acetyl coenzyme A
56
What enzyme combines choline and Acetyl coenzyme A to made ACh?
Choline acetyltransferase (ChAT)
Is also used as a diagnostic marker for ACh
57
What transporteer loads ACh into vesicles for release?
Vesicular Acetylcholine Transporter (VAChT)
58
What produces Botolimun toxin?
Clostridium botulinum
59
What does the Botulinum toxin do?
- Interferes with SNARE proteins which help with the docking and fusing process
- Doesn't allow the release from the synaptic vesicles
- Causes muscle paralysis and death
- Can be used in small doses (botox)
60
What synthesises Latrotoxin?
Black widow spider (males= diluted, females= concentrated)
61
What does Latrotoxin do?
- Makes pores on the membrane of the neurons, calcium then goes in and the cell gets stimulated to release ACh
- Causes cramps and twitching
- When a real ACh stimulus comes, the ACh has already been released and the vesicles are empty so the muscle cannot contract
62
What does AChE convert ACh into?
- Choline (can be recycled back into the presynaptic neuron)
- Acetate
63
Where other than the nerve and muscle can AChE be found?
Red blood cells
64
What is AChEs catalytic activity?
- Very high
- Each molecule degrades 25,000 molecules of ACh per second
65
What is BChE also known as?
Pseudocholinesterase because it is non-specific to ACh and can break down any similar esterases
66
Where is BChE found?
Mostly in the blood but also in the brain
67
What are 3 main groups of AChE inhibitors?
- Short acting- reversible, brief (10 mins)- used to diagnose Myasthnia gravis
- Medium acting (1-2 hours)- reversible, broken down more slowly, used to treat myasthnia gravis and glaucoma
- Irreversible- used as pesticides or chemical weapons
68
What is an example of a short-acting AChE inhibitor?
edrophonium
69
What are two examples of a medium acting AChE inhibitor?
- neostigmine
- physostigmine
70
What are the side-effects of AChE inhibitors?
- Actions of parasympathetic nervous system (bradycardia, hypotension, hypersecretion, bronchoconstriction, GI tract hypermotility, decrease intracocular pressure)
- SLUDGE syndrome
- Prolonged muscle contraction
71
What does SLUDGE syndrome stand for?
- S- salivation
- L- lacrimation (tears in the eyes)
- U- urination
- D- Diaphoresis (sweating)
- G- gastrointestinal upset
- E- emesis (vomiting)
72
What are two naturally occuring AChE inhibitors?
- Fasciculins (snakes)
- Physiostigmine/Esterine (Calabar bean)
73
What are fasciculins and what do they do?
- Are toxic proteins found in mamba snake venom
- They bind to AChE, blocking its activity
- They cause intense muscle fasciculation this paralysing or killing prey
74
What is phyostigmine and what does it do?
- Originally used to test witchcraft- if died=witch
- Reversible cholinersterase inhibitor
75
What is physiostigmine now used for?
- Treat glaucoma, myasthenia gravis, AD, delayed gastric emptying
- Antidote for anticholinergic drug overdoses (e.g. atroping)
76
What are two irreversible AChE inhibitors?
- Sarin gas- a chemical weapon which is an inhibitor of AChE
- Insecticides such as malathion and organophosphates
(both cause SLUDGE)
77
What was used in order to treat the irreversible AChE inhibitors?
Reactivators of the blocked enzyme such as pralidoxime which was developed as snake bit antidotes and protection agaisnt nerve agents
78
How does Pralidoxime act?
- AChE has two binding sites
- Organophosphate would bind to the esteric site
- Pralidoxime will then bind to the anionic site and to the organophosphate
- This changes the conformation and organophosphate will then detach so AChE is free to act again
79
What did Langley do in cholinergic receptor research?
- First to talk about receptors mediating the responses of the cells to transmitters
- If apply nicotine to the prepared muscle, then the muscle will contract even though wasn't attached to a neuron.
- Means the chemical was causing the contraction
80
What did Dale further not to Langley's discovery on nicotine?
The drugs muscarine and nicotine only partially mimiccked ACh effects therefore the muscarinic and nicotinic receptors were discovered
81
Where is muscarine extracted from?
The fly agaric mushroom amanita muscaria
82
What is muscarine?
It is a non-selective agonist of the muscaric AChR
83
What side-effects does muscarine cause?
SLUDGE, bradycardia, bronchoconstriction and abdominal cramping
84
What do CNS mAChRs do?
Regulate large number of important functions such as cognitive, behavioural, sensory, motor and autonomic processes
85
What do peripheral mAChRs do?
Mediate ACh effecrs in the parasympathetic nervous system such as decreasing heart rate, increasing smooth muscle contractility and glandular secretion
86
What are changed in mAChR levels linked to?
AD, PD, depression and schizophrenia
87
What is the structure of a muscarinic receptor?
Are metabotropic, GPCRs, with seven-transmembrane proteins
88
How many subtypes of mAChR are there?
5- M1-M5
89
What do M1, M3 and M5 mAChRs selectivery couple to?
Gq/G11= Increase PLCbeta, Ca, MAP kinases and decreased M current
90
What do M2 and M4 mAChRs preferentially activate?
Gi/G0= Increase MAP kinases, GIRK channels and decreases Adenylyl cyclase and voltage-operated Ca channals
91
Does activation of M1, M3 and M5 lead to inhibition or excitation?
Excitation- increases Ca
92
Does activation of M2 and M4 cause excitation or inhibition?
Inhibition- prolongs K channal opening so repolarisation takes longer
93
What type of ligand activates muscarinic receptors?
Agonists are parasympathomimetic- due to peripheral actions
94
What is an example of an agonist for muscarinic receptors?
Pilocarpine for glaucoma
95
What ligand is inhibitory for muscarinic receptors?
Antagonists are parasympatholytic- tend to be non-selective for sub-types
96
What are two examples of muscarinic receptor antagonists?
- Oxybutynin for overactive bladder and incontinence
- Ipratropium for asthma and COPD
97
What is atropine?
A competative, reversible antagonist of the mAChRs (non-selective)
98
Where is atropine synthesised?
- Mandrake plant
- Deadly nightshade
99
What does atropine cause?
mydriasis (pupil dilation), tachycardia, urinary retention, constipation and dry mouth
100
When is atropine used?
In surgery and as an antidote for nerve agent and pesticide poisoning
101
What is Nicotine?
A non-selective agonist of the nicotinic ACh receptor binding muscle and neuronal nAChRs in the peripheral and central nervous systems
102
What do the nAChRs function as?
- Ach-gated cation channels
- They are fast ionotropic receptors permeable to sodium, potassium and calcium ions
103
Where are nAChRs expressed?
Widely in the central and peripheral nervous systems
Can also be found in other tissues such as macrophages, epithelia, glial cells and keratinocytes
104
What are two types of nAChRs?
Muscular and neuronal
105
What is the structure of a muscular nAChR?
- Heteropentamer (5)
- Organised around a central pore in the membrane
106
What are the 5 subunits of a muscular nAChR?
- 2x alpha
- 1x beta 1
- 1x delta
- 1x gamma (embryo) or epsilon (adult)
107
What is the relative level of expression of each nAChR receptor based on?
Muscle innervation
108
How many helical transmembrane domains does the muscular nAChR contain?
M1-M4
109
What is a significant homomeric neuronal nAChR?
alpha 7- consists of 5 alpha 7 subunits
110
What is a significant heteromeric neuronal nAChR?
alpha4beta2- 5 subunits, 3 beta 2 and 2 alpha 4
111
What do differences in receptor stoichiometry configurations cause?
Differences in calcium permeability and agonist and antagonist sensitivity
112
What are the most common two neuronal nAChR configurations?
alpha4beta 2 and alpha 7
113
What are three actions for neuronal nAChR antagonists?
- Ganglion blocking agents- act on the autonomic nervous system (not used anymore because work on sympathetic and parasympathetic)
- NM blocking agents (competative)- act on neuromuscular junction
- Centrally-acting compounds to help people stop smoking
114
What is an example of a ganglionic blocking agent?
penthonium
115
What is an example of a neuromuscular blocking agent?
tubocurarine
116
What is an example of a centrally-acting compound?
bupropion or mecamylamine
117
What does curare do?
Blocks muscle nAChR, is a competative antagonist of ACh
When bound to a receptor curare elicits no response
118
What is a cure for curare?
AChE inhibitor
119
What is the NMJ?
Is the place of contact between a motor neuron and a muscle fibre
The motor neuron transmits a signal to the muscle fibre via a chemical synapse causing muscle contraction
120
What are the 6 steps of action at a NMJ?
- Action potential arrives and depolarises the neuron
- Caclium enters causing vesicles to form around the ACh
- Vesicles dock and fuse into the cell membrane. They release ACh into the synaptic cleft
- Ach binds onto the cholinergic receptors and another AP at the level of the muscle occurs causing the muscle to contract
- Agrin is also released from the presynaptic nerve terminal and binds to the LRP4, MuSK complex
- It makes a postjunctional fold where ACh receptors cluster, so when ACh arrives,, there are a lot of receptors waiting
121
What does the action of LRP4 and MuSK acheive in the NMJ?
- Formation of postjunctional folds
- Maintenance of the receptors
- Maintenance of the folds
122
What is myasthenia gravis?
- An autoimmune disease
- Autoantibodies against AChRs
123
What is neonatal myasthenia gravis?
- An autoimmune disease
- When maternal anti-AChRs antibodies are transferred to the foetus
124
How long does neonatal myasthenia gravis usually last?
3 months
125
What is neuromyotonia (Isaac's syndrome)?
- Autoimmune disorder
- Hyperexcitation of motor nerves- depolarisation is longer than normal upon an AP so more calcium leads to more ACh released and more contraction
- Tense muscles- does not lead to muscle weakness unlike the other autoimmune diseases
126
What are congenital myasthenic syndromes?
Mutations in presynaptic, synapticand postsynaptic proteins
127
How was myasthenia gravis discovered?
- Jon Lindstrom generated antibodies agains purified AChRs
- He injected it into rabbits and found that they go flat (muscles have become weak)- similar to myasthenia gravis
- This was the first indication that myasthenia gravis could be an autoimmume disease
128
What are the symptoms of myasthenia gravis?
- Muscular weakness
- fatigability especially after activity
- ptosis- eye lid muscle cannot keep open
- Bulbar and proximal issue where have trouble closing mough, swallowing and speech
129
What is the prevalence of myasthenia gravis?
150-300 per 1,000,000 individuals
130
What are the three ways in which things go wrong within myasthenia gravis?
**There are no differences at the level of the nerve terminal- only at the level of the muscle**
- Loss of junctional folds (reduced in size significantly)
- Leads to a reduction in cholinergic receptors
- Enlargement of synaptic cleft- means when ACh is released, it can be lost to diffustion
131
What happens in myasthenia gravis when there are repeating APs?
Leads to progressively decreasing **muscle** action potentials, with decreasing muscle power
132
In what percentage of myasthenia gravis patients are AChR antibodies found?
- 70%
- Bind to the receptor and stop it from functioning by disrupting the communication
133
In what percentage of myasthenia gravis patients are MuSK antibodies found?
- 1-10%
- Important for clustering and folding
134
In what percentage of myasthenia gravis patients are LRP4 antibodies found?
- 1-5%
- Important for folding and clustering
135
What is the first choice treatment for myasthenia gravis?
Symptomatic drug therapy
136
What are the two types of symptomatic drug therapy in myasthenia gravis?
- AChE inhibitors - stop the breakdown of ACh in the NMJ
- If AChE is not enough such as in MuSK antibodies then drugs that increase ACh presynaptic release
137
What is an AChE inhibitor used in myasthenia gravis?
- Pyridostigmine (most used)
- Neostigmine
138
What is a drug used in myasthenia gravis that increase presynaptic release and how does it work?
- 3, 4-diaminopyridine
- Blocks K channels at the level of the nerve terminal which extends the duration of the AP which means more calcium enters the presynaptic neuron so there is more ACh released
139
What are the second choice treatments for myasthenia gravis?
- Immunosuppressive drug therapy- the source of the problem to stop the antibodies
- Thymectomy- the source of the problem is located in the thymus where t cells mature so can remove the thymus
140
How many genes have been found that code for congenital myasthenic syndromes?
30
141
What is the principle clinical feature of congenital myasthenic syndromes?
Fatigable weakness
142
What is the UK prevalence of congenital myasthenic syndromes?
9.2 cases per million children under 18
143
What are the three types of congenital myasthenic syndromes?
- Presynaptic
- Synaptic
- Postsynaptic
144
What is the syndrome, gene and proportion of presynaptic CMS?
- ChAT deficiency (key enzyme in making ACh from choline and acetyl)
- CHAT
- 6%
145
What is the syndrome, gene and proportion of synaptic CMS?
- Endplate AChE deficiency
- COLQ- Attaches AChE to the synaptic cleft
- 13%
146
What are the 3 syndromes,5 genes and proportions of postsynaptic CMS?
- Primary ACh deficiency, CHRNA, CHRNB, CHRND, CHRNE, 33%
- Kinetic defecits AChR (slow channel and fast channel syndrome), CHRNA, CHRNB, CHRND, CHRNE, 18%
- Others, various, 30%
147
How do endplate AChE deficiencies occur?
Mutation in COLQ gene which encodes for the triple-stranded collagenic tail anchoring AChE to the synaptic basal lamina
148
What do COLQ mutations lead to?
- Prolonged synpatic currents and action potentials because of extended residence of ACh in the synaptic space
- Because the role of the tail is to anchor AChE in the cleft. If AChE is not attached, it floats away
- Leads to muscle damage and weakness of all voluntary muscles
149
What causes primary AChR deficiency?
- Not as many receptors as would expect as disrupts how well the muscle contracts
- Mutations in alpha, beta, delta and epsilon nAChR subunits
- Most occur in epsilon as is less severe than heterozygous or homozgous low-expressor mutations in the other three so less likely to be fatal
150
How does slow channel syndrome manifest?
- Changes in the receptor functioning- do not work as well
- Receptor stays open for too long so the current lasts longer and decays slowly
151
How does fast channel syndrome manifest?
- Caused by recessive mutation in one allele of a nAChR subunit
- There is a decreased probability that the AChR is opened by physiological concentrations of ACh
- The channel closes too quickly meaning the endplate current goes up normally but goes down too quickly to prodice an AP (repolarises too fast)
152
How can fast channel syndrome be diagnosed?
No clinical clues point to the diagnosis of a fast-channel syndrome; in vitro microelecrode studies are required
153
What are two cholinergic agonists the are used to treat congenital myasthenic syndromes?
- Pyridostigmine- AChE inhibitor
- Amifampridine- Increases Ach release by blocking K channels at the presynaptic neuron. This lengthens the depolarisation of the neurons so increases Ca and ACh is increased
154
What is one method of treating slow channel syndrome?
- Long-lived open-channel blockers of AChR ion channel
- Helps to close the channel quicker
- Could make fast channel syndrome worse (be careful)
155
What are two long-lived open-channel blockers of AChR ion channel?
- Fluoxetine
- Quinidine
156
What are two adrenergic agonists used to treat congenital myasthenic syndromes?
- Salbutamol
- Ephedrine
- (Not clear what the mechanisms are)
157
What is essential when chosing the therapy for congenital myasthenic syndromes?
A molecular diagnosis
158
In what year and by whom was AD discovered?
- Alois Alzheimer
- 1902
159
Who was the first case study of AD?
- Augustine Deter- 'I seem to have lost myself'
- She died 5 years after diagnosis
- Alzheimer kept a detailed diary of her symptoms and observations of her progession
160
What was AD originally labelled?
Disease of forgetfulness
161
What was an early erronous observation about the onset of AD?
Originally considered to be pre-senile dementia in younger people, but now we know it is the most common form of dementia in the elderly
162
What is the percentage of dementia cases that AD makes up?
The most common neurodegenerative disease accounting for more than 80% of all dementia cases
163
How many current AD sufferers are there worldwide and how many will this rise to in 2050?
- 50 million
- Will triple to 152 million
164
What is the cost of dementia in the UK and how much will it be i the next 25 years?
- Current cost is 26 billion pounds
- 2040= 55 billion pounds (will double)
165
How does AD initially manifest?
Symptom pattern begins with progressive decline in ability to remember new information and cognitive function
There is a progression from episodic memory problems to global decline of cognitive function
166
Where in the brain does AD effect?
- Progressive loss of synpatic neurons and atrophy in the
- Hippocampus (memory)
- Frontal cortex (decision making and logical functioning)
- Temporoparietal cortex (sensory processing)
167
What accumulates outside the cells in AD?
Amyloid beta plaques around the neurons
168
What accumulates inside the cells in AD?
Hyperphorsphorylated microtubules associated with tau protein in the form of intracellular neurofibrillary tangles
169
What are 7 proposed multifactorial pathogenesis of AD?
- Malfunctioning Cholinergic transmission
- Excessive protein misfolding and amyloid beta aggregation
- Oxidative stress and free radical formation
- Metal dyshomeostasis where metals like zinc and copper promote AB formation
- Excitotoxic and neuroinflammatory processes
- Tau pathology (neurofibrillary tangles)
- Genetic associations which affect susceptibility but are not the cause
170
What is the cholinergic hypothesis of AD?
- Degeneration of neurons from the cholinergic nuclei in the basal forebrain region (especiallly the nucleus basalis of Meynert) and their terminals (projections) to the hippocampus
- Causes hippocampal atrophy and ventricle enlargement
171
At the cellular level, what 5 things occur in the cholinergic hypothesis?
1. Learning, memory and attention reduction
2. ChAT enzyme undergoes reduced expression
3. Therefore choline and acetyl do not form ACh and there is reduced levels
4. The binding parameters are disrupted so it doesn't bind as well with the receptor- causing the transmission of information to be impaired
5. AChE (decreases) and BuChE (rises) ratio becomes inbalanced leading to an accumulation of AB plaques
172
What is the non-amyloidogenic pathway of the amyloid hypothesis of AD?
- Amyloid precursor protein (APP) is broken down by two enzymes
- Alpha secretase
- Gamma secretase
- This causes the production of P3
173
What is the amyloidogenic pathway of the amyloid hypothesis of AD?
- Amyloid precursor protein (APP) is broken down by two enzymes
- Beta secretase
- Gamma secretase
- The outcome is a larger protein which is sticky
- The monomers of this amyloid beta protein stick together forming oligomers then stick again to form protofibrils then again to form fibrils and then again to form plaques
- This is pathological
174
What are the 4 outcomes of amyloid beta plaques?
- Neuritic injury (neuron damage)
- Formation of NFT via tau protein ?
- Neuronal dysfunction and cell death
- Synapse loss and brain atrophy
175
What are the steps of the neuroinflammatory theory of AD?
1. Accumulation of CNS pathology such as AB primes microglia
2. this causes them to release inflammatory cytokines and chemokines
3. These continue to prime more microglia
4. The elevated inflammatin may lead to tau pathology
5. Having inflammation for a period of time leads to neurodegeneration and neuron loss
6. After a long duration of activation the microglia burn out and turn into a state which stops them working
176
What is the normal action of tau within the axon?
Regulates microtubule dynamics and axonal transport
177
What is the normal action of tau within the nucleus and dendrites?
- Unclear dendrite mechanism
- In the nucleus it helps to maintain genomic DNA (repairs)
178
Where in a cell is tau found?
- Dendrite
- Nucleus
- Axon
- Presynaptic terminal
179
What occurs in the axon in pathogological tau?
Hyperphosphorylated Tau detaches from microtubules leading to microtubule dissassembly- the transport of chemicals along the axon is disrupted
180
What happens in the presynaptic terminal when there is pathological tau?
There is synaptic dysfunction and loss of vesicles
181
What happens in the dendrites (post-synaptic location) when there is pathological tau?
Post-synaptic dysfunction and synaptic loss
182
What happens in the nucleus when there is pathogological tau?
It can no longer enter the nucleus therefore it cannot maintain the DNA so there is damage
183
What happens when pathological tau aggregates?
Deterioration of neuronal function and the spread of tau pathology
Because it is sticky it aggregates and then it leaves the cell seeding the pathology
184
What other pathology do authors suggest that tau aggregates behave like?
May have similar properties to prions disease
185
What is the main therpeutic strategy at treating AD?
Aimed at re-establishing functional cholinergic neurotransmission using AChE inhibitors- 4 out of 5 licenced drugs in the UK do this
186
Between which years were there no new drugs for AD?
2003-2021 = 18 years
187
What are 5 new therapeutic strategies for treating AD?
- Therapies against amyloid plaques
- Tau-targeted therapies
- Multi-targeted-directed ligands
- Multifunctional activity drugs
- Repositioning drug development
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What is repositioning drug development?
Using a drug already in the market to treat AD
An advantage is that there is less time and money spent
189
What is an example of a repositioned drug for AD?
- Nilvadipine
- Currently used to treat hypotension
- Preclinical studies showed it decreases AB plaques
- But it failed trials in AD because it did not improve cognition
190
What is anti-amyloid beta immunotherapy?
Creating antibodies at different stages of the amyloidogenic process such as
- Against APP
- Against monomeric amyloid beta
- Against soluble amyloid beta oligomers
- Against insoluble amyloid beta fibrils
- Against AB carrier proteins and transporter channels
191
What are the two methods of giving anti-amyloid beta immunotherapy?
- Passively- via injection
- Actively immunising- via vaccine
192
In addition to anti-AB immunotherapies what is another therapy against AB?
Gamma and beta secretase inhibitors
These have all failed clinical trials
193
What was the first approved drug for AD approved in 18 years and what does it do?
- Aducanumab 2021
- Monoclonal antibody that vinds to amyloid aggregates in both oligomeric and fibrillar sstates
- Decreases levels of amyloid plaques
- Controversial approval because this has not led to cognitive benefits
194
What is the first new drug to slow cognitive decline in early-stage AD patients and what does it do?
- Lecanemab 2022 - FDA 2023
- Monoclonal antibody that binds to aggregated forms of AB peptide to block the formation of amyloid plaques
- Controversial as causes brain haemorrhage and has caused fatalities
195
What was the second drug to slow cognitive decline in early-stage AD patients and what does it do?
- Donanemab 2023- FDA in process
- Monoclonal antibody targetting amyloid proteins, resulting in AD-associated cerebral amyloid plaque load
196
What is the cost of Aducanumab?
$56,000 per year
197
What is the cost of Lecanemab?
$28,000 per year
198
What is an issue with the cost of new AD drugs in the UK?
NHS cannot afford the prices therefore resulting in the rejection of lecanemab (also cognitive benefits are small and there is high risk)
199
How many years before AB can tau pathology be spotted?
20 years
200
Why is it thought that tau pathology may be the cause of AB pathology?
Because you cannot have amyloid wihtout tau but you can have tau without amyloid
201
What are 3 strategies aimed at preventing tau pathology?
- Inhibition tau fibril formation (chemical)
- Promotion abnormal tau clearance (antibodies, vaccination)
- Inhibition tau aggregation
202
What are Multi-targeted-directed ligands (MTDL)?
- Dirty drugs
- Instead of targetting one site to produce therapeutic effects, these target many targets causing enhanced therapeutic effect
203
What are 2 bennefits of MTDL?
- Simplified pharmacokintetic as there is only one drug to digest and metabolise
- Simplified therapeutic regimen as only have to remember one drug
204
What are two limitations of MTDL?
- Only tried in vitro and in animals
- Multiple side effect profiles (can combat by giving in lower doses than a single target drug)
205
How can a MTDL be made?
Join active parts of different molecules making a new molecule with different properties
206
What is the composition of MTDL3?
- ChE inhibitor
- Metal-chelating
- MAO inhibitor
- Iron-chelating compound with antioxidant and neuroprotective activity
207
What are multifunctional activity drugs?
Drug has one target but has multiple therapeutic effects
Same bennefits as MTDLs
208
What is an example of a multifunctional activity drug?
- nAChR-selective ligands
- alpha4beta2 decreased in AD (high ACh affinity), compounds targeting this receptor are the first to be developed to improve cognition
- alpha7 is also decreased in AD, (low ACh affinity), agonists improve performance in learning and memory-related tasks
