Alzheimer's Disease: Pathophysiology, Treatment, and Galantamine

This essay provides a comprehensive overview of Alzheimer's disease (AD), a prevalent neurodegenerative disorder affecting neurons in the brain. It delves into the pathophysiology of AD, highlighting the roles of amyloid precursor protein (APP), amyloid beta protein, and tau protein in the development of the disease. The essay discusses various treatment approaches, including the use of drugs like donepezil, memantine, and galantamine. It specifically examines the mechanism of galantamine, including its effectiveness in animal models using the 5XFAD mice model. The essay also explores the role of acetylcholinesterase inhibitors and NMDA receptor antagonists in managing AD symptoms and slowing down the progression of neural degeneration. Furthermore, it discusses the impact of the disease on cognitive functions and the potential for restoring cognition deficits. The essay concludes by summarizing the current understanding of AD and the therapeutic strategies employed to address this complex condition.

Running head: STUDY ON ALZHEIMER’S DISEASE
Study on Alzheimer’s Disease
Name of the Student
Name of the University
Author Note

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A neurodegenerative disorder refers to a huge range of condition that mainly affect the
neurons of the brain in the animal or human body. Neurons are not capable of regenerating
themselves like the normal cells. As a result, a damage in a neurons cannot be repaired, rather its
starts to degenerate gradually and at last the nerve cells or the neurons are completely destroyed.
The neurodegenerative disorders are mainly associated with the dementia problem among the
patients of neurodegenerative disorders. The most common neurodegenerative disorders are
Alzheimer’s disease (AD), Parkinson’s Disease (PD), Spinal muscular atrophy (SMA), Motor
neuron disease (MND) (JPND, 2019). In this essay, the Alzheimer’s disease, its pathophysiology
is highlighted. The drugs that can be used to treat the disease condition is also discussed.
However, AD cannot be cured but the process of gradual degeneration of the neurons can be
prevented by using specific drugs. There are a few drugs that can be used to slow down the
process of neural degeneration. The most common drugs are donepezil that is an inhibitor of
Acetyl cholinesterase, memantine that is the antagonist of NMDA receptor, galantamine can be
used as drug in treatment of AD. In this essay, the mechanism of galantamine is highlighted.
Firstly, the effectiveness on an animal model is discussed and then the usefulness of the drug on
the human body is also described in the later part of this essay.
AD is one of the most common neurodegenerative disorder. It is assumed that amyloid
precursor protein (APP) is one of the causative factors for AD. However, there are other
hypothesis that supports the pathophysiology of the AD and they are cholinergic hypothesis,
inflammation hypothesis and tau hypothesis. According to the amyloid hypothesis, the APP is
generally cleaved by the enzymes named alpha-secretase and then it is again processed by two
enzymes named gama and beta secretases. As a result the production and clearance rate of the
amyloid peptide is altered and generally clearance rate is reduced. The amyloid proteins are then

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deposited continuously into the soluble coalesce and oligomers that is responsible for the
formation of insoluble beta-sheet. This newly formed beta-sheets are gradually deposited in the
diffuse senile plaques. Some studies also supported that the amyloid beta protein-42 are formed
due to the cooperative activities of the astrocytes and the neurons of that astrocytes (Kumar &
Singh, 2015). Moreover the formation of the amyloid beta protein-42 also can promote the
oxidative damage of the neuronal cells. In addition to this, the hyper phosphorylation of the tau
protein is also promoted by the amyloid beta protein 42. Behind the onset of AD, the intracellular
neurofibrillary tangles (NFTs) are also equal responsible along with the amyloid beta protein. In
a normal condition, the tau protein is ineffective and is responsible for keeping the cytoskeleton
in a proper condition and shape. The abnormal behavior of the protein is due to the misfolding of
the proteins and that causes a conformational change in the actual protein structure of the tau
protein and this results aberrant deposition of the fibrillary structures in to the neurons. This
alteration of the tau protein can alter the stabilization of the microtubules. There are a few
enzymes that are responsible for the excessive phosphorylation of the tau protein and they are
mainly Glykogen synthase kinase-3 (GSK-3), Mitogen activated protein kinase (MAPK), Cyclin
dependent kinase ( CD5). The deregulations of these enzymes are directly associated with the
hyper phosphorylation of the tau protein inside the neurons. In addition to this, Ca+2/
CalModulin-dependent protein kinase II (CamKII) can also cause the hyper phosphorylation of
the tau. GSK-3 beta is accountable for the normal and as well as altered condition of the tau
protein in the neuronal cells of the body. The tau protein is mainly phosphorylated on the
residues named ser396, Thr231, Ser404, Ser199 and Ser413 (Jouanne, Rault, & Voisin-Chiret,
2017). In the pathological conditions like AD, the tau protein is phosphorylated in the specific
regions that contain the PHFs. In case of AD the tau protein is generally 3 to 4 times more

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phosphorylated when it is compared to the normal condition of the brain. Due to the hyper
phosphorylation of the protein the tau protein loses its ability to bind with the microtubules and
as a result there is a conformational changes that leads to formation of PHFs. The tau protein
fragments are easily aggregated. The phosphorylated tau proteins cannot bind to the tubulin also.
The hyper phosphorylated tau is the primary component of the straight filaments, NFTs, PHFs,
neutrophil threads and also of the plaque associated dystrophic neuritis in the brain of an AD
affected patient. The concentration of the NFTs is associated with the degree of the dementia in
the AD patients. In addition to this, due to formation of the PHFs, the excessive phosphorylation
of the tau protein is also promoted and this will ultimately causes conformational changes of the
tau protein (Jouanne, Rault, & Voisin-Chiret, 2017).
In case of the treatment of AD, there are a few drugs that can be used and they are mainly
memantine, galantine, and donepezil. The drug memantine is used to treat the patients with
moderate to severe AD and it has seen that this drug has become successful to combat against the
disease. Memantine is a voltage dependent, uncompetitive NMDA receptor antagonist. The
molecule has moderate binding affinity with the receptor and it has also the capacity of rapid
unblocking-blocking capacity. The unusual property of the memantine allows the molecule to
integrate into the glutamatergic signaling pathway and as a result it makes the NMDA receptor
dysfunctional in case of AD. In a healthy nervous tissue, the channels of the NMDA receptor are
blocked by the magnesium ions (Mg+2). Whenever, there is a strong glutamate presynaptic
signal, the post synaptic membrane is depolarized and the voltage dependent Mg+2 dependent
channel opens. As a result the, extracellular calcium ions from the synaptic cleft have the access
to enter the post synaptic region through those opened channel. In case of AD, due to the
amyloid beta protein and the glutamate, there is a continuous low level signal that lowers the

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membrane potential. This causes depolarization of the neuron even by a very low level of
stimulus and the blockage of the NMDA receptor by the Mg+2 ion is removed. This causes the
Ca+2 ions to enter and there is a continuous influx of those ions. In an electrophysiological
studies it is seen that, the memantine can bind with the channels of the NMDA receptor (Alam et
al., 2017). As memantine binds in a voltage dependent manner, in AD, the continuous
stimulation is also unable to remove the barrier of memantine barrier that is in a condition
stimulating condition memantine can block the NMDA channel. As a result, there is no such
Ca+2 influx like the diseased condition. Moreover, when there is strong glutamic signal like
normal condition, the memantine is released from the channel, of the NMDA receptor and there
is a normal Ca+2 influx into the post synaptic membrane. By this method, memantine reduce the
dysfunctional glutamate signaling and in the same time it also help in recognizing the actual
physiological signaling. In addition to this, it is also seen that, memantine also protect the
neurons from excitotoxicity due to continuous glutamate discharge. Memantine is also associated
with the reduction of glutamate reuptake. Memantine also help to reduce the level of learning
deterioration and helps in restoring the cognition deficits, amount of soluble and insoluble
amyloid beta proteins (Alam et al., 2017). The donepezil molecule can also counter the AD in an
effective manner. Therefore it has different mechanism from the memantine molecule. It is a
acetyl cholinesterase inhibitor (AChEIs) that is altering the actions of the acetylcholine and it is
also used to treat the AD from the mild to extreme condition. This molecule acts mainly by
inhibiting the action of the acetylcholinesterase that is hydrolyzing enzyme that can hydrolyze
the Ach. As a function of this molecule, the amount of Ach is reduced as the enzyme is
hydrolyzed into choline and acetate. As a result, the concentration of the Ach is reduced in the
synaptic cleft. The adequate amount of the Ach will not bind to the post synaptic receptor of the

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acetylcholine. The molecules like donepezil are inhibiting the steps of hydrolyzation of the Ach.
The main aim of the AchEIs are to maintain the level of Ach in the post synaptic cleft of the
neurons. However, if the acetylcholinesterase is unable to perform its function, the amount of the
Ach in that region. It is seen that, lower amount of the Ach level in the neurons are associated
with the dementia that is one of the most important of the AD. Moreover, it is seen that, the
higher concentration of the Ach in the brain can enhance the number of the nicotinic Ach
receptors on the cholinoseptive neurons (Imamura et al., 2015). Not only that, it is also capable
of improving functions of various other neurotransmitter related systems for example : glutamate
level is increased with the enhanced level of the nicotinic Ach receptors. The AchE is associated
with the enhancement of the cholinergic neurotransmission and even the patients who are in the
advanced stage of their disease also shows response to the drug (Zemek et al., 2014). Donepezil
and galantamine work by inhibiting the acetylcholinesterase. In this particular assignment, the
galantamine will be discussed specifically (Matsuzono et al., 2015).
The galantamine is a well-established drug for the treatment of the AD that are mild to
moderate in nature (Ohnishi et al., 2014). In a study for understanding the effectiveness of the
drug, an animal model was used. In this study, the 5X Familial Alzheimer’s Disease (5XFAD)
was used and along with this, the amount of amyloid beta plaque was also examined. There are a
few advantages of using the animal model in this study. The used animal model in the study is
5XFAD. In this mouse model, the mouse line co-overexpresses APP along with the three FAD
mutations that are K670N/M671L, I716V, V717I and also PS1 with 2 FAD mutations M146L
and L286V and this process is performed under specific control of neuron specific thy-1
promoter. This model is able to address a various type of AD features including reduced anxiety,
memory dysfunction, and extensive extracellular plaque formation. Moreover, the formation of

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the plaque is seen at the two months of age in case of this mouse model and in this model
selective neuron loss is also observed. For these features, 5XFAD has become an important
research model for examining the effectiveness of the galantamine in case of AD (Bhattacharya
et al., 2014).
In the study by Bhattacharya et al. (2014), the used mice model over expressed both the
mutant human APP (695) along with human PS1 harboring two FAD mutations and the Florida (
I716V), Swedish ( K670N, M671L), London ( V717I) familial AD mutations. In this study,
galantamine was used in 10-12 week old mice by dissolving the drug in the drinking water at a
concentration of 12mg/l during first four weeks, in the next three weeks the dose was 60mg/l or
36mg/l during four weeks followed by 120mg/l for next three weeks (Bhattacharya et al., 2014).
The behavioral experiments were conducted after eight weeks of the treatment. The water
deprivation was stopped before the 30-60 minutes of the test so that the concentration of the
galantamine in the blood of the mice. In the open fields the transgenic mice spent more time in
the corner of the maze in comparison with the control non transgenic mice models. Not only that,
the transgenic mice had reduced latency of entering the dark compartment while comparing with
the control mice models. The reduced latency of entering the dark area confirmed the formation
of the long term memories among the transgenic mice models. Fear conditioning was also tested
in this experiments and it was seen that, the transgenic mice showed more freezing in this tests in
compared to the control group of the study. However, the context memory was not significantly
different from the non-transgenic control group. After the treatment with galantamine the
transgenic mice showed more preferences for staying in the corners like normal mice and
reduced avoidance of the center among the transgenic mice was also noted. Treated transgenic
mice showed normal level of time spending in a light illuminated area (Bhattacharya et al.,

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2014). The overall study showed that the treatment with galantamine was able to improve the
behavior of the mice model in an open field and it was able to restore the light-dark avoidance
paradigm partially. The transgenic mice that were treated with the drug had significantly lower
number of plaques in enterohinal cortex and hippocampus. In hippocampus, 19% and 25% less
plaques were found among male and female transgenic mice. In the enterohinal cortex the
amount was almost 32% and 33% less among the males and females respectively (Bhattacharya
et al., 2014). The study of Jiang et al. (2015), also supported the effectiveness of the galantamine
study and they showed that there was significant differences (P< 0.05) in cognitive and
behavioral pattern of the AD patient. In another study it was seen that galantamine had become
successful to reduce the mortality among the AD patients and also improve the cognition power
of the patients (Hager et al. 2014).
Lastly, it can be concluded that, although galantamine itself is an effective drug, the
combination of galantamine and memantine can also be used in case of treatment of AD. Study
supported that combine use of galantamine and memantine can improve the cognitive deficits,
moving time and resting time. Whereas individual use of those drugs are not capable of showing
all of the effects. The drug study of galantamine can also be effective in case of human as several
human model study also supported the effectiveness of the galantamine (Zemek et al., 2014).
In this essay, the usage of galantamine drug on the AD is discussed and along with this,
the effect of this specific drugs on a specific animal model is also highlighted. Not only are that,
a specific study on that animal model along with the results and analysis of that study discussed
briefly as well. The chosen study overall showed that, galantamine is very much effective in the
transgenic 5XFAD mice model in comparison to the non-transgenic control mice group that was

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chosen for that particular study. The galantamine can also be used in case of the human as it
showed effectiveness while it was used in human model.
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