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Alzheimer’s Disease

The brain is a complex organ; it is responsible for the initiation and control of
many bodily processes through electrochemical signalling. Disorders of this
complex organ result in significant incapability of the persons affected to
lead a normal life. The brain is formed of many types neurons that act
together to transmit information through specific neurotransmitters, and the
loss of some specific neurones will result in specific symptoms. For example
in Parkinson’s Disease dopamnergic neurones are lost in the substantia nigra
which is needed in controlling of muscles so tactile and co-ordinated
movements are lost.

Alzheimer’s Disease (AD) has had awareness recently, from famous authors
developing it such as Terry Pratchett. In the UK up to 750,000 people suffer
from dementia of which half suffer from AD. AD is a neurodegenerative
disorder that progressively destroys brain cells (Fig.1.). These loss of brain
cells lead to symptoms in patients such as forgetfulness (also a symptom of
normal aging), severe memory loss, dysphasia, loss of numerical abilities,
anxiety and mood changes, psychosis, hallucinations, delusions and
aggressiveness. Alois Alzheimer was the first to report AD in 1906. Alois
carried autopsies of patient revealing specific pathology. The pathology
revealed cellular debris around nerve cells (senile plaques) and bundles of
tangled nerves (neurofibrillary tangles).

Fig.1. Shows a cross section of a normal brain in comparison to an

Alzheimer’s sufferer. Note: loss of neuron in areas of the brain responsible
for language and memory in the Alzheimer’s sufferer.

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The cause of Alzheimer's disease are largely unknown, however there are
factors that have been linked with the disease, such as, age, with an ever
ageing population AD is the fourth most common cause of death in the
western world (the older a person is the more possible the person will suffer
Alzheimer's), genetics, it has been shown that AD has a genetic component
therefore, parents can transfer it to their offspring and females are more
likely to suffer than men (5). There are other factors that have been optionally
led to AD, which include a protein molecule dysfunction and, a head injury
early in life which can increase the risk of developing AD amongst others. AD
is a loss of neurons and shrinkage of brain tissue, especially in the
hippocampus and basal forebrain. Acetylcholine is a stimulatory
neurotransmitter chemical which plays a significant role in memory
formation. It is also used in the control of sensory input signals and muscular
control. When acetylcholine released by nerves to a muscle it makes muscles
contract. It is made from the precursor choline. Also, numerous drugs affect
the production and release of this neurotransmitter. A deficiency in
acetylcholine is linked to Alzheimer’s disease. There are three mains
features in AD condition; neurofibrillary tangles, amyloid plaques (Fig. 2.)
and granulovacuolar degeneration.

Fig. 2. Comparison of a normal neuron and an AD sufferers neurons.

A neurofibrillary tangle is when the structure of a neuron changes and a
large amount of protein fibre is tangled up inside nerve cells called Tau. Tau,
is a certain number phosphate molecules attached to it, binds to
microtubules and appears to stabilise them. Where in AD, an unusually large
number of extra phosphate molecules attach to tau, this resulting in
“hyperphosphorylation,” tau separate from the microtubules and starts to
come together with other tau. These tau form structures called paired helical
filaments, which can become entangled with one another, forming tangles
within the cell. The microtubules can split up in the process, breaking up the

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neuron’s internal transport network. This collapse damages the ability of

neurons to communicate with each other (Fig. 3.).

Fig. 3. Shows the formation on tau tangles in both a healthy neuron and in
an AD neuron which subsequently results in the death of the neuron in an AD
sufferer.

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Amyloid plaques are another characteristic of AD. Amyloid plaques are

insoluble, hard protein fibre that accumulates in the nerve cell as shown in
fig.2. The structures of this amyloid plaques are consistent of the Aβ
fragment of amyloid precursor protein (APP). In the outside of the cell
membrane, specific enzymes cut, or cleave, APP into separate fragments,
these enzymes are called A-secretase, β-secretase, and γ-secretase,
depending on which enzyme is involved the fragment of APP where the
cleaving occurs. The formation of amyloid plaque (fig. 4.) begins with
enzymatic cleavage of the amyloid precursor protein (APP) by β-secretase,
then cleavage by γ-secretase generates the Aβ38-42 peptides, of which Aβ42 is
the most neurotoxic(6).The toxic type of Aβ that is composed of 42 amino acid
residues, is the product of the proteolytic cleavage of β-amyloid precursor
protein (βAPP). The sequential cleavage of βAPP is performed by β- and γ-
secretase, where β-secretase is responsible for the start of the Aβ42
formation process (7). Granulovacuolar degeneration is when fluid-filled
vacuoles are seen host inside the nerve cell, specifically in the triangular
shaped cells of the hippocampus.

Fig. 4. Shows the formation of the amyloid plaque by APP cleavage via β-
and γ- secretase forming neurotoxic Aβ fragment that aggregates to form
amyloid plaques. The formation of these plaques occurs when there is an
imbalance between formation and clearance of Aβ in the brain.

Drugs have been developed for the treatment of Alzheimer’s however these
drugs are unable to reverse the pathology associated with the disease,
Rather they are intended to slow down the progress. There are three

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pharmacological strategies that are used in the treatment of AD, the use of
acetylcholine precursor as lectin choline, drugs that increase the release of
acetylcholine such as Hydergine and finally cholinesterase inhibitors such as
donepzil.
Acetylcholine is a neurotransmitter at synapses in the brain, in both the
central and peripheral nervous systems. They assist in the carrying chemical
messages in the brain through carrying the action potentials across the
synapses. It is needed in the formation of memory and learning. Once
acetylcholine carries its message to the receiving cell it is broken down via
the action of enzymes called acetylcholinesteraes, acetylcholine is broken
down to its precursors of acetyl (in the form of acetyl coenzyme A) and
choline which is then recycled to acetylcholine by choline acetyltransferases.
In Alzheimer’s disease acetylcholine producing cells are either damaged or
destroyed resulting in the reduction or impairment of the amount of
acetylcholine needed to carry the message across the neuron. Due to this
decrease in level of acetylcholine in the brain of an Alzeimer’s sufferer a
potential treatment used to alleviate some symptoms is to increase the
amount of acetylcholine in the brain. This can be achieved to the reduction
of breaking down of acetylcholine in the neuron via the inhibition
cholinesterase. Cholinesterase inhibitors such as donepzil work by inhibiting
the breaking down of acetylcholine by cholinesterase which results in an
increase in the level of acetylcholine at the synaptic junction increasing the
possibility of an action potential at the specific synapse. By maintaining the
acetylcholine levels in the brain by using cholinesterase inhibitors may
compensate for the loss of functioning brain cells, cholinesterase inhibitors
seem to also have other benefit, they seem to increase the responsiveness
of the neuron to acetylcholine. The most popular drugs used to treat AD are
acetylcholinesterase (AChE) inhibitor. AChE inhibitor work by blocking the
enzyme that is accountable for the degradation of the neurotransmitter
acetylcholine in the synapse (fig. 5). In patients that experience decrease
level of the neurotransmitter, AChE inhibitors are used to treat their AD.

a) b)

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Fig. 5. a) The mechanism of action of acetylcholine at the synapse. b) The

action of acetylcholine and the sites which inhibitors act on.

Another drug used in the treatment of AD is memantine. Memantine works

by regulating the activity of glutamate. Glutamate plays an important role in
learning and memory by activating NMDA receptors, to allow calcium ions
into the nerve cell in controlled amounts. Calcium is needed for information
storage. However, excessive amounts of glutamate can allow more calcium
into the cell resulting in cell death. Memantine’s role is to protect cells from
excess glutamate by partially blocking NMDA receptors. The recent
treatments for AD only serve to improve the side-effects without curing the
disease; therefore researchers seek new methods for curing AD(1).

Recent researchers in pharmacological therapies for the treatment of AD are

ongoing trails (9), e.g. γ-Secretase Inhibitors. A study has been in progress on
drugs which inhibit the γ-secretase, as a possible treatment AD; this has
shown to be a promising new drug. By inhibiting the γ-secretase cleavage of
APP will stop and prevent the sequential cleavage step of Aβ, therefore will
decrease or stop the amount of amyloid plaque developed. The study has
been focused on two ways of changing γ-secretase activity.

The first technique developed is the inhibiting the creation of Aβ fragments

of all lengths, while the other method is to increase the formation of the
shorter less pathogenic form of the Aβ fragments. There are several
inhibitors that are shown to be successful in stopping the Aβ production,

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however, the solution is not as clear cut. γ-secretase is not only responsible
for the production of Aβ but also it is responsible for the cleavage of vital
membrane proteins needed for cell survival.

LY-450139 is the first γ-secretase inhibitors to go through clinical trails. LY-

450139 was found to decrease plasma levels of Aβ, nevertheless it was
unable to lower the cerebrospinal fluid level of Aβ. LY-450139 lacked the
specificity for the cleavage of APP and only low doses could be used due to
the damaging side effects on the healthy cells. γ-secretase is involved in
cleavage of several other substrates other than APP, these includes Notch (a
transmembrane cellular protein involved in cell signalling). Notch requires a
signal to bind to extracellular domain that causes in its cleavage and release
of the domain. Notch then goes transmembrane cleavage by γ-secretase,
which then releases the intracellular fragment named Notch Intracellular
Domain (NICD) which then enters the nucleus causing transcriptional
changes in the cell. Studies carried on mice with LY-450139 on its inhibition
of γ-secretase showed decrease in Aβ level, however with other harmful
effects. The mice had large impairments of the spleen, thymus and intestine.
These side effects were due to the inhibition of Notch cleavage which
resulted in gastrointestinal toxicity and interference of maturation of both B-
and T- lymphocytes. Hence, from these initial studies a different angle must
be taken if these enzymes were to be targeted in the treatment of AD. Other
γ-secretase targets could be amined at to affect its cleavage, which will not
hamper the effects of cleavage on Notch.

The development of less amyloidgenic plaques is one of the main approaches taken
by researcher. In order to avoid the problems linked with requirement of inhibition
specificity for APP by γ-secretase inhibitors. In addition a new generation of more
specific inhibitors are being investigated as alternative recent new possible
treatments, which are non-steroidal anti-inflammatory drugs (NSAIDs). This has
been in consideration for treatment of Alzheimer's disease (AD) for more than two
decades (10). NSAIDs inhibits generation of the pathogenic amyloid-β(1–42) peptide
(Aβ42) separately of the inflammatory cyclooxygenase (COX) pathway, then in
progress drug development efforts are focussed on improvement of the COX-
independent Aβ42-lowering activity, this will help to prevent amyloid pathology and
secondary inflammatory reactions and to avoid the clinical side-effects associated
with inhibition of COX. (fig7).

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Fig. 7. the diagram shows new possible protective mechanisms of NSAIDs in

AD. It works by changing production of the Aβ 42 peptide, which a key factor
in development of AD is process responsible for synaptic dysfunction and
neuronal loss in AD. Aβ42 is generated by first processing amyloid protein
through β- secretase then through γ-secretase complex. Aβ42 can oligomerise
and form senile plaques which then lead to microglial activation, synaptic
dysfunction; dystrophic neurons and neuronal loss (10). NSAIDs may be
protective in AD since it interacts with various targets in these pathways and
have effects on one or all of these pathways. The main pharmacological
effect of NSAIDs is to inhibit cyclooxygenase (COX, enzymes that produce
inflammatory prostaglandins), this inhibition is reported to improve the glial
inflammation and subsequently the slow amyloid pathology. Some NSAIDs
have been shown to modulate γ-secretase activity directly, resulting in
selective reduction of amyloidogenic Aβ42 peptides. (10)

A study has been carried out by Bher et al, on Sulidac sufide and R-flubipfen
which are NSAID-like compound were tested for their ability to specifically
inhibit γsecretase activity on APP. These two compounds decrease overall
production of both Aβ42. For R-flurbiprofen, Aβ42 production was reduced by
75% when compared to the control. The study also showed that increasing
the concentration of either R-flurbiprofen decreased the rate of production of
both Aβ40 and Aβ42. The mechanism of R-flurbiprofen inhibition, which
showed that secretase enzyme rate decreased as the concentration of drug
increased.

There are several drugs that under investigation that has shows some
affiance on treating or slowing progress of AD, such as the compositions of
Vitamins E and C plus Ibuprofen may protect against Alzheimer’s (14).
Estrogens have been indicated to lower rate of AD. In addition, the studies

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confirmed an improvement in metabolism of women taking oestrogen.

Aspirin is anti-inflammatory drugs it have been under investigation before
and have not cognitive benefits of these drugs for patients with disease,
although the trials were of short duration short period of 2 years and the
disease may have been too advanced to allow detection of benefits (15). There
many more drugs have been examined find cure/improvement to the
disease.

In conclusion, the means of information concerning Alzheimer’s disease is

fast rising through the use of many biochemical techniques that aim at
determining the root causes of this debilitative neurological disorder. From
Alzheimer’s discovery of abnormal protein deposits in brain slides, both the
β-amyloid plaques and neurofibrillary tangles have been researched
extensively in the expectation of discovering cures to stop of their
developments and debilitating effects. Aβ protein fragments building up in
intercellular spaces and cause neuronal death. These fragments are created
through the action of secretases, the pathological causes of AD are the
erroneous cleavage of the amyloid precursor protein by γ-secretase.
Through many well designed and well thought out experiments, it was found
that γ-secretase is a mulitpass transmembrane aspartyl protease, which
gave further insight into the mechanism for Aβ production. Understanding
the biochemical mechanisms allows researchers to create therapeutic agents
that could halt γ -secretase activity, and thus the progression of AD.
Currently, two major approaches are in clinical trials to test their efficacy
towards halting Aβ production. The first method is through the use of
Nonsteroidal anti inflammatory drugs, which induce cleavage of the amyloid
precursor protein at a locus that will produce a smaller fragment that are
less prone to accumulation. The second approach came from the knowledge
that γ-secretase contains an ATP binding domain. By blocking this site, it
was found that the production of Aβ proteins can be halted without stopping
other important biological processes of γ-secretase, including Notch
cleavage.

The secondary cause of AD, has also been found in several other
neurological diseases, is the accumulation of neurofibrillary tangles within
the neuron. NFTs results from the hyperphosphorylation of the tau protein.
Tau normally binds to, and stabilises microtubules in neurons, but when they
are phosphorylated in the segments that usually bind the tubulin filaments
their binding ability is decreased. Destabilized tau proteins begin
accumulating in the cell and disrupting cellular transportation and

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communication. Continuing knowledge is being amassed concerning the

kinases responsible for the hyperphosphorylation so that appropriate drugs
can be designed to halt their phosphorylation activity.

As more researches and clinical trials develop for AD, the prospective of
producing novel and more effective drugs is increased. Major findings
concerning the inheritability factors are also being researched. However, the
largest risk or contributing factor to developing AD is increasing age; there
are some inheritable risk factors that increase the risk for developing AD.

References:
1) Page. Curtis. Sutter. Walker.Hoffman, (2002); Integrated
pharmacology, Chapter 14 page 262.

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2) Rang, H.P; Dale, M.M.; Ritter J,(2003); Fifth edition

Pharmacology,Chapter 34 page 494-496.
3) Amyloid Plaques Are Surprisingly Dynamic, Dr. Gandy is Mount Sinai
Professor of Alzheimer’s Disease Research, Mount Sinai School of
Medicine, New York City, Journal Watch Neurology June 3, 2008
4) Lliffe Steve and Burns Alistair, (2009) Alzheimer’s disease. BMJ. 21st of
5) Dailyscience (2008) Alzheimer’s disease: Women Affected More often
than Men.
6) Daniel D. Christensen, MD, (2007) Alzheimer’s disease: Progress in the
Development of Anti-amyloid Disease-Modifying Therapies.CNS Spectr.
12(2):113-123
7) Snowden,(2009), The Development of Pharmacological Treatments for
the Neurodegenerative Disorder Alzheimer’s disease.
http://www.bama.ua.edu/~chem/seminars/student_seminars/spring09/
albury-sem.pdf
8) François Sella, André Nieoullon, Géraldine Michel, Bernard François
Michel, Lucette Lacomblez, Hugo Geerts, Alexandra Delini Stula, Régis
Bordet, Danièle Bentué-Ferrer, Hervé Allain (2005) Pharmacology of
Alzheimer’s Disease: Appraisal and Prospects.
9) Martin Citron, (2004), β-Secretase inhibition for the treatment of
Alzheimer’s disease –promise and challenge, Pharmacological Sciences
Vol.25 No.2 and information of the drug LY450139 Dihydrate
http://www.alzforum.org/drg/drc/detail.asp?id=108
10)Sascha Weggen, Mark Rogers and Jason Eriksen, (2007), NSAIDs: small
molecules for prevention of Alzheimer's disease or precursors for
future drug development?, Volume 28, Issue 10
11)Magdalena Sastre, Ilse Dewachter, Steffen Rossner, Nenad
Bogdanovic, Evan Rosen, Peter Borghgraef,Bernd O. Evert, Lucia
Dumitrescu-Ozimek, Dietmar R. Thal, Gary Landreth, Jochen
Walter,Thomas Klockgether, Fred van Leuven, and Michael T. Heneka.
(2004), Nonsteroidal anti-inflammatory drugs repress β-secretase gene
promoter activity by the activation of PPAR.
12)Dirk Beher, Earl E. Clarke, Jonathan D. J. Wrigley, Agnes C. L. Martin,
Alan Nadin,Ian Churcher, and Mark S. Shearman, (2009), Selected Non-
steroidal Anti-inflammatory Drugs and Their Derivatives Target γ-
Secretase at a Novel Site ,J. Biol. Chem., Vol. 279, Issue 42.
13)Dr Freestone notes to outline the essay.
14)Zakaria Ammache, MD, (2005) Update on Treatment of Alzheimer
Disease, adaptation Galvin et al., Neurology 2005;65:559-564.19

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15)Jae Hee Kang, instructor, Nancy Cook, associate professor, JoAnn

Manson, professor, Julie E Buring, professor, Francine Grodstein,
associate professor. Low dose aspirin and cognitive function in the
women’s health study cognitive cohort. BMJ

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