BB30044: Existing and future treatments for Alzheimer’s
disease (RW)
Current Therapeutics
Loss of neurotransmitters in AD:
Loss of synapses in AD means loss of neurotransmitters.
Measurement of neurotransmitter changes in post-mortem AD brains show
changes in many neurotransmitter systems (acetylcholine showed 65%
decrease compared to control, glutamate 20%, 5HT/serotonin 60%,
noradrenaline 65%). Widespread alterations reflect the heterogeneous
pathology of the disease.
Most notable neurotransmitter change in terms of therapy is
Acetylcholine: a significant loss of ACh is seen in AD brains. Loss of
cholinergic neurons is associated with diminished cognitive function
characteristic of AD.
Loss of other neurotransmitters such as serotonin and noradrenaline link
to other symptoms of AD such as anxiety, depression and paranoia.
Loss of Acetylcholine in AD:
Acetylcholine is synthesised from Choline and AcetylCoA by the action of
the enzyme choline acetyltransferase (ChAT)
Acetylcholine is then packaged into synaptic vesicles by the vesicular
acetylcholine transporter (VAChT).
ACh is released into the synaptic cleft from synaptic vesicles and in
response to depolarisation. Diffuses across the synaptic cleft and interacts
with various receptors (muscarinic and nicotinic) on the pre- and post-
synaptic membrane.
The concentration of ACh in the synapse is rapidly reduced by the action
of Acetylcholinesterase (AChE) and possibly butyrylcholineresterase
(BuChE) at the extremes of the synapse. This recycles choline for
resynthesis.
Cholinergic cell bodies are found in the basal ganglia and brain stem. Cells
in the nucleus basalis of Meynert (nbM) send axons to the cortex, while
those in the medial septum innervate the hippocampus and ER.
In AD, a loss of nerve terminals results in reduction in synaptic ACh.
Therapy must address this ACh deficit.
Acetylcholinesterase inhibitors inhibit ACh degradation to maintain
ACh transmission in AD. 3 principle drug treatments are currently
available. Up until 2011, these drugs were only available for moderate-
severe AD, but were then approved for mild-moderate AD because an
inhibitor should be used in early disease when the majority of cholinergic
neurons are still intact.
1. Aricept: produced by Eisai and co-marketed with Pfizer, first drug to
be licensed in the UK specifically for AD. Thought to confer notable
benefit for 2/3 patients – efficacy depends on the heterogeneity of
disease and when treatment is received.
2. Exelon: produced by Novartis, the second drug licensed in the UK
specifically for AD.
, 3. Reminyl: was co-developed by Shire and the Janssen Research
Foundation. Natural product origin: derived from the bulbs of
snowdrops and narcissi. The third drug licenced in UK specifically for
AD.
4. Tacrine: no longer widely used due to significant side effects.
The limitation of these drugs was illustrated in the same clinical trials that
proved their efficacy!
Original clinical trials show change in mental performance in AD patients
either receiving Aricept treatment or placebo. Placebo patients showed a
decline in cognitive performance over time, which was reversed in a dose-
dependent manner in those receiving Aricept.
However, after study week 12, the treated group began to show a decline
in cognitive performance at a similar rate to placebo group. Why?
Extension of the trial showed that after the drug was washed out of
patients at week 20, all groups showed the same cognitive performance.
This means that the drug provided symptomatic benefit but did NOT limit
disease progression.
Loss of glutamate in AD:
Memantine was produced by Merz and marketed in Europe by Lundbeck.
It is the newest of the AD drugs. Licenced for moderate-severe AD in 2011.
Acts as an NMDAR antagonist, thereby targeting glutamate deficit and
increasing glutamate levels.
In post-mortem AD brains, there is reduction in the function of vGluT
transporters in vesicle membranes which package glutamate into vesicles.
This reduces glutamate concentration in vesicles. Nerve stimulation
therefore gives a lower peak of glutamate transmission.
Coincident with this, there is impaired reuptake of glutamate due to
damage in glia and transporter proteins that clear glutamate out of the
synapse.
Reduced peak glutamate release and slower reuptake means that the
sharp peak of glutamate synaptic signalling is lost (higher ‘background’
signal) disrupting glutamatergic transmission.
Differences between Memantine and other NMDAR antagonists:
High-affinity NMDAR antagonists such as MK-801 block NMDARs in
response to pathological increased glutamate ‘background’, but it also
prevents glutamate signalling in response to synaptic activity
(depolarisation).
They therefore produce significant side effects at therapeutic doses e.g.
psychotomimetic effects.
Memantine acts like Mg2+: it is a moderate-affinity NMDAR antagonist
which prevents signalling due to background glutamate ‘noise’. However,
it has voltage-dependent blocking kinetics, so there is no NMDAR block
upon synaptic activity (depolarisation).
Combination therapy:
Combination of AChEI (Acholinesterase inhibitor) and Memantine (NMDAR
blocker) both increased the cholinergic signal and reduced the glutamate
signal ‘noise’, providing collective benefit.
disease (RW)
Current Therapeutics
Loss of neurotransmitters in AD:
Loss of synapses in AD means loss of neurotransmitters.
Measurement of neurotransmitter changes in post-mortem AD brains show
changes in many neurotransmitter systems (acetylcholine showed 65%
decrease compared to control, glutamate 20%, 5HT/serotonin 60%,
noradrenaline 65%). Widespread alterations reflect the heterogeneous
pathology of the disease.
Most notable neurotransmitter change in terms of therapy is
Acetylcholine: a significant loss of ACh is seen in AD brains. Loss of
cholinergic neurons is associated with diminished cognitive function
characteristic of AD.
Loss of other neurotransmitters such as serotonin and noradrenaline link
to other symptoms of AD such as anxiety, depression and paranoia.
Loss of Acetylcholine in AD:
Acetylcholine is synthesised from Choline and AcetylCoA by the action of
the enzyme choline acetyltransferase (ChAT)
Acetylcholine is then packaged into synaptic vesicles by the vesicular
acetylcholine transporter (VAChT).
ACh is released into the synaptic cleft from synaptic vesicles and in
response to depolarisation. Diffuses across the synaptic cleft and interacts
with various receptors (muscarinic and nicotinic) on the pre- and post-
synaptic membrane.
The concentration of ACh in the synapse is rapidly reduced by the action
of Acetylcholinesterase (AChE) and possibly butyrylcholineresterase
(BuChE) at the extremes of the synapse. This recycles choline for
resynthesis.
Cholinergic cell bodies are found in the basal ganglia and brain stem. Cells
in the nucleus basalis of Meynert (nbM) send axons to the cortex, while
those in the medial septum innervate the hippocampus and ER.
In AD, a loss of nerve terminals results in reduction in synaptic ACh.
Therapy must address this ACh deficit.
Acetylcholinesterase inhibitors inhibit ACh degradation to maintain
ACh transmission in AD. 3 principle drug treatments are currently
available. Up until 2011, these drugs were only available for moderate-
severe AD, but were then approved for mild-moderate AD because an
inhibitor should be used in early disease when the majority of cholinergic
neurons are still intact.
1. Aricept: produced by Eisai and co-marketed with Pfizer, first drug to
be licensed in the UK specifically for AD. Thought to confer notable
benefit for 2/3 patients – efficacy depends on the heterogeneity of
disease and when treatment is received.
2. Exelon: produced by Novartis, the second drug licensed in the UK
specifically for AD.
, 3. Reminyl: was co-developed by Shire and the Janssen Research
Foundation. Natural product origin: derived from the bulbs of
snowdrops and narcissi. The third drug licenced in UK specifically for
AD.
4. Tacrine: no longer widely used due to significant side effects.
The limitation of these drugs was illustrated in the same clinical trials that
proved their efficacy!
Original clinical trials show change in mental performance in AD patients
either receiving Aricept treatment or placebo. Placebo patients showed a
decline in cognitive performance over time, which was reversed in a dose-
dependent manner in those receiving Aricept.
However, after study week 12, the treated group began to show a decline
in cognitive performance at a similar rate to placebo group. Why?
Extension of the trial showed that after the drug was washed out of
patients at week 20, all groups showed the same cognitive performance.
This means that the drug provided symptomatic benefit but did NOT limit
disease progression.
Loss of glutamate in AD:
Memantine was produced by Merz and marketed in Europe by Lundbeck.
It is the newest of the AD drugs. Licenced for moderate-severe AD in 2011.
Acts as an NMDAR antagonist, thereby targeting glutamate deficit and
increasing glutamate levels.
In post-mortem AD brains, there is reduction in the function of vGluT
transporters in vesicle membranes which package glutamate into vesicles.
This reduces glutamate concentration in vesicles. Nerve stimulation
therefore gives a lower peak of glutamate transmission.
Coincident with this, there is impaired reuptake of glutamate due to
damage in glia and transporter proteins that clear glutamate out of the
synapse.
Reduced peak glutamate release and slower reuptake means that the
sharp peak of glutamate synaptic signalling is lost (higher ‘background’
signal) disrupting glutamatergic transmission.
Differences between Memantine and other NMDAR antagonists:
High-affinity NMDAR antagonists such as MK-801 block NMDARs in
response to pathological increased glutamate ‘background’, but it also
prevents glutamate signalling in response to synaptic activity
(depolarisation).
They therefore produce significant side effects at therapeutic doses e.g.
psychotomimetic effects.
Memantine acts like Mg2+: it is a moderate-affinity NMDAR antagonist
which prevents signalling due to background glutamate ‘noise’. However,
it has voltage-dependent blocking kinetics, so there is no NMDAR block
upon synaptic activity (depolarisation).
Combination therapy:
Combination of AChEI (Acholinesterase inhibitor) and Memantine (NMDAR
blocker) both increased the cholinergic signal and reduced the glutamate
signal ‘noise’, providing collective benefit.
