Biochemical Origins of Alzheimer’s Disease
With Treatment Techniques
Nikolai Wajda
Senior Comprehensive Paper
The Catholic University of America
Spring 2007
Abstract:
Alzheimer’s disease (AD) is a neurodegenerative disease caused by
irregular protein formations in the brain leading to neuronal loss and ultimately affecting
the patient’s cognitive ability and memory. AD affects nearly 4.5 million Americans, and
this number is expected to continue to rise1. The pathological manifestations of AD
occur in the neurons and are two-fold; the primary cause is the accumulation amyloid
(Aprotein depositions, which aggregate into pathogenic plaques. The second is the
accumulation of paired helical filaments that form into neurofibrillary tangles (NFTs).
A plaques result from the sequential cleavage of the amyloid precursor protein (APP) by
-secretase and secretase. NFTs result from the hyperphosphorylation of tau, a
stabilizing component of microtubules. Based on current understanding of the
Apathway, two major strategies will be discussed that aim at decreasing the deposition
of Aplaques in the brain. In the first approach, non-streroidal anti-inflammatory drugs
alter the APP cleavage site by -secretase to produce less amyoidogenic plaques. A
second method aims at inhibiting -secretase activity on APP through allosteric inhibition
of ATP binding.
2
Introduction:
The first diagnosis of the disease that would eventually carry his name was done
by Alois Alzheimer while treating a woman who showed early signs of dementia, which
included progressive memory loss, delusions, and hallucinations2. Alzheimer, a German
psychiatrist working at a mental institution in Frankfurt, Germany, made the critical
breakthrough leading to the discovery of the pathological causes of this disease when he
applied Max Bielschowsky’s silver staining technique to brain slides of the woman after
her death. In the slides, Alzheimer identified two abnormal protein products
accumulating in the neurons. While the composition was not known at that time, the
components would later be identified as -amyloid plaques and neurofibrillary tangles
(NFTs), the hallmark causes of AD. amyloid is an irregular protein product that
accumulates into large plaques in extra-cellular spaces and inhibits intercellular
communication, ultimately leading to neuronal death. NFTs result from the
hyperphosphorylation of tau, which leads to the destabilization of microtubules in
neurons. This allows the hyperphosphorylated tau to accumulate into tangled protein
masses that blocks both intracellular communication and transportation of nutrients in the
cell.
Drugs are being developed that target these pathological causes. Many
biochemical techniques have been utilized for the development of therapeutics that will
inhibit the production of these pathological proteins. In this paper, nucleotide binding
site inhibition and cleavage site alteration by nonsteroidal anti-inflammatory drugs
(NSAIDs) will be discussed.
3
Production of Amyloid Plaques by Protease Activity
Amyloid-plaques result from the cleavage of the amyloid precursor protein
(APP) by a family of proteinases, termed secretases. The gene encoding APP is located
on chromosome 21, which is consistent with the predominance of plaques developing in
patients with Down’s Syndrome3. The normal function of APP is not well understood,
but it is believed that APP could act as a cell-surface receptor, could participate in cellcell adhesions, or could promote neuritic growth. APP is a transmembrane protein
consisting of 770 Amino acids; the protein has both intra- and extra- cellular segments.
Three sites for secretase cleavage occur on APP, secretase cleaves APP at AA 687 in
the extracellular region, secretase cleaves APP at AA 671 in the extracellular region,
and -secretase cleavage occurs at various locations in the transmembrane region.
cleavage precludes production of the amyloidogenic A proteins, however, sequential
cleavage of APP by and secretases produces the amyloidogenic A proteins4.
Amyloid-is a normal protein product, with an unknown function, that is formed
by the cleavage of APP by secretases. Two routes exist for the sequential cleavage of
APP, the first pathway produces the normally secreted product, p3, while the second
results in the pathological amyloid plaques6. The transmembrane region of APP is
between amino acids 700-723; the N-terminus, amino acids 1-699, is extracellular while
the COOH terminus, amino acids 724-770, is in the cytoplasm of the cell. When APP is
cleaved by -secretase after Lys687, the result is the release of a large soluble ectodomain
fragment ( -APPs) leaving the 83 residue COOH-terminal fragment (APP-CTFor C83)
with a transmembrane, extracellular, and an intracellular region. APP-CTF is
subsequently cleaved by -secretase at either Val711 or Ala713, which results in p3, a non4
pathogenic peptide fragment consisting of either 26 or 24 amino acids; a second protein
fragment, AICD, remains embedded in the membrane (Figure 1).
The alternate route for proteolytic cleavage of APP begins with -secretase
cleavage after Met671. This cleavage results in the secretion of a large soluble
ectodomain fragment (-APPs) and the retention of a 99-residue COOH-terminal
fragment (APP-CTFor C99). APP-CTF is then cleaved by -secretase at either Val711
or Ala713. This cleavage is important because if C99 is cut at position 711 it will result in
A40 while if APP is cut position 713 it will result in A424 (Figure 1). Cleavage also
results in AICD.
Figure 1: The cleavage of amyloid precursor protien by  secretases.4
The amyloidogenic nature of A fragments is dependent upon the -secretase
cleavage site. In studies of the brains of Down’s syndrome patients, who often develop
the trademark plaques young in age, it was found that A42 aggregates much more
5
rapidly than A40. In patients fifty years or younger it was found that only 6.3% of senile
plaques were A40, while in older brains, fifty or older, the amount of A40 increased to
42%5. A42 has two additional hydrophobic amino acids than A40; the presence of
isoleucine and alanine increase the amyloidogenic property of the fragments leading to
increased aggregation4.
Tau forms Neurofibrillary Tangles Following Hyperphosphorylation:
Tau proteins are a normal cellular product existing in six different isoforms. In
healthy neurons, tau binds to and stabilizes microtubules (MTs) as well as promotes
tubulin assembly and polymerization. Tau is most prominent in neurons because MTs
form the axons that allow for intracellular transportation of neurotransmitters and
nutrients. The disruption of microtubules leads to the inability to transport nutrients and
other vital materials in the cell, and through the accumulation of neurofibrillary tau the
ultimate result will be neuronal death.
Tau is phosphorylated in areas that surround MT binding repeats; thus increased
tau phosphorylation negatively affects tau’s ability to bind and stabilize MTs7.
Hyperphosphorylation leads to both gain and loss of tau activity that results in
neurotoxicity. Hyperphosphorylated tau destabilizes MT binding and increases tau-tau
interactions. Destabilized MT does not transport the necessary nutrients to other parts of
the neuron. An example of this is that destabilized MTs cannot transport
neurotransmitters from the cell body to the synapse where they can be released. Cutting
off a neuron’s ability to communicate with other cells effectively isolates it, causing it to
die. The increased tau-tau interactions of hyperphosphorylated tau causes the formation
of paired helical filaments that constitute neurofibrillary tangles (NFT’s). Paired helical
6
filaments are composed of two strands of filament twisted around one another with a
periodicity of 80 nm and a width varying from 8 to 20 nm7.
Cyclin dependent kinase 5 (Cdk5) is one of many kinases active in the
hyperphosphorylation of Tau. A cyclin-like membrane protein, p35, regulates Cdk5’s
phosphorylation activity by anchoring it to the plasma membrane. Calpain, a protease,
cleaves p35 into two fragments, p10 and p25; P10 anchors the active p25-Cdk5 complex
to the plasma membrane. Upon cleavage, the active p25-Cdk5 complex is unregulated
and free to phosphorylate throughout the cytoplasm (Figure 2). The p25-Cdk5 complex
increases phosphorylation and decreases the binding ability of tau on microtubules8,9.
Tau that is phosphorylated by P25-Cdk5 has reduced binding to microtubules and causes
the collapse of microtubule and formation of NFTs10.

Figure 2: The Cdk5, a kinase responsible for phosphorylation of Tau, is regulated
by cofactor p35.8

Risks Factors
The largest risk factor for the development of AD is increasing age. After 65
years of age, the incidence and prevalence of Alzheimer’s disease doubles every 5 years.
7
Genetic studies have been able to isolate inheritable factors contributing to AD, as well as
genetic mutations, which increase the risk for developing AD. Other than the fact that
autosomally dominant variety of AD is early in onset, the phenotypic expression of
familial versus sporadic AD is difficult to distinguish. There are four known genetic
factors which are related to the amyloid- pathway, the inheritance of the E4 allele of
apolipoprotein, or mutations in either Presenilin-1 (PS1), Presenilin-2(PS2), or
APP11,12,13.
Mutations in certain genes influence the development of A plaques
Missense mutations in the APP gene, in the PS1gene, or in the PS2 gene increase
the likelihood for developing Alzheimer’s disease. The gene encoding the amyloid
precursor protein is located on chromosome 21; missense mutations arising in this gene
that have been shown to confer an increased risk to AD. Missense mutations in the APP
gene increase the overall amount of Athrough the alteration of cleavage sites for the
processing of proteases (Figure 3). Missense mutations in APP, however, are considered
very rare and are found in only about two dozen families. It is believed that these
mutations effect proteolytic activity by the secretases because the mutations are all
located either directly before or directly after the secretase cleavage sites4.
8
Figure 3: Missense mutations occurring in APP which lead to the production of
A4
Double Mutations occurring before the -secretase site (K670N and L671M)
induce -secretase cleavage, and allows for increased amounts of the A precursor. Five
mutations occur on the COOH-terminal side of the -secretase cleavage site(I714T,
V715M, I716V, and I,G,F,L717V); these mutations increase the production of A,
which is the A form that most readily forms into plaques. Three APP mutations occur
inside the  and  cleavage sites (A692G, Q693E, and N,K,G694D); these mutations
increase the aggregation properties of all Aresidues
Missense mutations in the presenilin genes also increase the risk for developing
AD. So far, there are 75 known missense mutations in the PS-1, which is located on
chromosome 14, and only three to PS-2, located on chromosome 1, which are known to
cause AD. Mutations in the PS-1 gene cause the most common form of dominant early
9
onset familial AD. PS-1 mutations selectively increase precursor C99 cleavage by secretase to produce more A42.; A42 is a more amyloidogenic peptide compared with
A4014. In its complete and functional form, -secretase consists of PS-1 or PS-2,
nicastrin (nct), Aph-1 and PEN-2. PS-1 is found to play a vital role in the enzymatic
cleavage of APP by -secretase. PS-1 is made up of 9 transmembrane domains, and is
activated as the result of endoproteolysis. Endoproteolysis occurs in domain 7 of
presenilin, and creates the N-terminal fragment (NTF) and the C-terminal fragment
(CTF). The full length PS-1 protein is short lived, wheras the processed protein has a
much longer half life, suggesting that cleavage is necessary for function15.
Determining the structure of -secretase
The necessity of all four of these proteins for -secretase activity was proven
following the expression of the genes encoding for these proteins in Saccharomyces
cerevisiae by Steiner et al16. S. cerevisiae does not contain -secretase, so it is possible to
address the question of which components of the complex are necessary for activity by
selectively introducing the four components. An APP based protein that contains a
sequence analogous to the -secretase cleavage site was synthesized in order to report secretase activity. This protein is bound to GAL4, a transcription factor for βgalactosidase (β-gal). Cleavage of C1–55–GAL4 after co-expression of functional γsecretase is expected to liberate GAL4 from the cytosolic side of the membrane. GAL4
then translocates to the nucleus where it activates transcription of the Escherichia coli
LacZ gene, which encodes β-gal14. β-gal breaks down the sugar lactose, producing a blue
10
color that can be measured and quantified. In this experiment, the presence and intensity
of the blue coloring is a test for -secretase cleavage of C1–55–GAL4 (Figure: 4).
Figure 4: B-Gal activity to determine components of functional -secretase.14
GAL4: Expression of GAL4 protein as a control shows high B-Gal activity
PS1wt: Expression of the PS-1 without Nct, APH-1, or Pen 2 showed no b-gal activity
PS1wt: Expression of the PS-1 with Nct, APH-1 and Pen 2 showed high b-gal activity
PS1d3854A: Expression of a functionally inactive PS-1 with Nct, APH-1, and Pen 2
showed almost no activity
No NCT: Expression of PS-1, APH-1, and Pen 2 without NCT showed almost no activity
No APH-1: Expression of PS-1, Nct, and Pen 2 without APH-1 showed almost no activity
No PEN-2: Expression of PS-1, Nct, and APH-1 without PEN-2 showed almost no
activity
No PS1: Expression of Nct, APH-1, and PEN2 without PS-1 showed no activity.
The only complex that showed significant cleavage of the APP-like substrate
leading to -galactoside activity was the complete complex containing PS-1, nicastrin
(nct), Aph-1 and PEN-2. When the complex lacked even one of these components,
11
activity was significantly decreased16. In further experiments with mice, the results
showed that deleting PS-1 leads to the reduction of -secretase activity16. The vital
discovery that PS-1 was required for producing A led researchers to question how PS-1
cleaves APP.
Wolfe et al. determined that two aspartate residues on PS1 were required for the
endoproteolytic and γ-secretase function. Introducing mutations to two intermembrane
aspartates in PS-1, D275A and D385A or D275E, reduced the production of both A40
and A42 while increasing the amounts of A precursor substrates C83 and C99. The
Asp to Ala double mutations led to substantially less total A (mean 57 +/- 3%) and
A42(53 +/- 4%) than cell lines expressing wild-type PS-117. D275E mutations was done
to see if removing the negative charge of the Asp had a detrimental effect on protein
folding that could have resulted in decreased cleavage. However, Glutamate, with its
negative charge still resulted in decreased A production 17. An increase in
concentrations of both APP-CTFand -APPs shows that both the  and  secretases are
still active, while the decreased concentrations of A means that -secretase is unable to
process these fragments, contributing evidence that the aspartates are required for
proteolytic activity. The double mutations of the aspartates also halted endoproteolytic
activity of presenilin17. Levels of A produced from cells with aspartate double
mutations were found to be similar to levels where PS1 was deleted17. Furthermore, the
activity of the enzyme requires a slightly acidic pH, which contributes more evidence to
this theory of PS-1 as an aspartyl protease18.
12
Current Treatment:
Current therapeutics are insufficient for the treatment of AD. The most popular
drugs used to treat AD are acetylcholinesterase (AChE) inhibitors. AChE inhibitors
block the enzyme responsible for the degradation of the neurotransmitter acetycholine in
the synapse. As a result of neuronal loss associated with AD, patients suffer from
decreased levels of this neurotransmitter, thus inhibiting the activity of AChE, more
acetylcholine will be present at the synapse. The second method used for treating AD is
memantine, which is an uncompetitive NMDA receptor antagonist. Memantine regulates
glutamate, a messenger chemical required for information processing, storage and
retrieval. Glutamate binds to NMDA receptors, and allows calcium to enter nerve cells
in controlled amounts. Calcium influx is required for information storage, however, too
much glutamate overstimulates NMDA receptors and allows too much calcium into cells,
disrupting cells and causing death. Memantine protects against excess glutamate activity
by partially blocking NMDA receptors. The current treatments for AD only serve to
ameliorate the side-effects without curing the disease, therefore researchers seek novel
methods for curing AD1.
-Secretase Inhibitors
Research targeting the enzyme -secretase as a potential target for combating AD
has shown some promise as well as some setbacks. Inhibiting -secretase cleavage of
APP would prevent the second step in the sequential cleavage of the Aandthus
decrease the amount of amyloid plaque developing in the brain. Research has focused on
two approaches for altering -secretase activity. The first method is by inhibiting the
creation of A of all lengths, while another is to increase the formation of shorter, less
13
pathogenic Afragments. Several inhibitors have been found to be successful in halting
A production; developers, however, hit a roadblock when complications arose due to the
fact that -secretase is also being responsible for cleaving other membrane proteins vital
to cellular survival. LY-450139, the first -secretase inhibitor to go through clinical trials
was found to decrease plasma levels of A however; it was unable to lower
cerebrospinal fluid levels19. While this drug was found to be partially effective and well
tolerated, LY-450139 lacked the desired specificity for the cleavage of APP and dosages
had to be kept low because of the detrimental side effects that it would have have. secretase is active in the cleavage of several substrates other than APP, including Notch,
a transmembrane cellular protein active in cell signaling. Notch first requires a signal to
bind to its extracellular domain that will cause cleavage and the release of this domain.
Notch then undergoes transmembrane cleavage by -secretase, which releases an
intracellular fragment termed, Notch Intracellular Domain, NICD, which enters the
nucleus and causes transcriptional changes in the cell20-21. In vivo studies of a -secretase
inhibitor, LY-411,575, by Wong et al., showed decreased production of A, but also
showed deleterious effects in mice. Large impairments of the spleen, thymus, and
intestine were observed. The most pronounced side effects of the -secretase inhibitor
were caused by the inhibition of Notch cleavage, ultimately leading to gastrointestinal
toxicity and interference with the maturation of B- and T-lymphocytes21-22. From these
initial studies into the inhibition of secretase, a new direction must be taken for drugs
aimed at this enzyme. The new direction must be one that can inhibit the production of
amyloid plaques without affecting the cleavage of other -secretase targets. Two
approaches will be discussed below, one will be the use of NSAID’s which aim to alter
14
the cleavage site of -secretase and thus produce shorter, less amyoidal plaques while the
second will seek to inhibit -secretase activity on APP through allosteric inhibition of
ATP binding.
Nonsteroidal Anti-Inflammatory Drugs
The formation of less amyloidogenic plaques is an approach taken by researchers.
Instead of inhibiting the secretion of all amyloid plaques, certain drugs will aim at
decreasing the percentage of the longer, and more amyloidogenic plaques.
In order to circumvent the problems associated with the lack of inhibition
specificity for APP by -secretase inhibitors, a new generation of more specific inhibitors
are being investigated. These drugs exhibit greater selectivity towards the inhibition of
APP cleavage and allow for normal enzymatic cleavage towards Notch. NSAIDs have
been shown to decrease the amount of the more amyloidogenic A42 by altering the
binding site of -secretase. In a study conducted by Beher et al., sulindac sulfide, an
NSAID, and R-flurbiprofen, a NSAID-like compound were tested for their ability to
specifically inhibit -secretase activity on APP.
A
B
Figure 5: Structure of sulindac sulfide (A) and R-flurbiprofen (B).23
The two compounds decreased overall production of both A40 and A42.
(Figure: 5, A: sulindac acid and B: R-flurbiprofen). For R-flurbiprofen, A42 production
was reduced by 75% when compared to the control. The study also showed that
15
increasing the concentration of either R-flurbiprofen decreased the rate of production of
both A40 and A42 (Figure 6:C and D). Kinetic assays were undertaken to determine the
mechanism of R-flurbiprofen inhibition, which showed that secretase enzyme velocity
decreased as the concentration of drug increased. A Lineweaver-Burke plot from the
inhibition kinetic assays of A42 by R-flurbiprofen demonstrated a noncompetitive mode
of inhibition. As the concentration of drug was increased, the plot showed a decrease in
Vmax with an while the Km remained the same, data consistent with noncompetitive
inhibition (Figure 6:E). These data suggest that the NSAIDs bind at a site independent of
the substrate binding site23.
Figure 6: Certain NSAIDs decrease the rate of A production via noncompetitive
inhibition.23
A) Decrease in A levels from treatment with Sulindac Sulfide
B) Decrease in A levels from treatment with R-flurbiprofen
C) -secretase velocity (production of A40) decreases upon treatments with Rflurbiprofen
D) -secretase velocity (production of A42) decreases upon treatments with Rflurbiprofen
E) Lineweaver-Burke Plot showing decrease in Vmax while Km remains the same
16
Further evidence that the binding of NSAIDs occurs at a site other than the
catalytic site was performed using a transition state radioligand, which bind to the
catalytic site of the enzyme. Competition studies using tritiated Merck A, the transition
state analog inhibitor, showed that both R-flurbiprofen and sulindac sulfide displace the
radioligand. The noncompetitive nature of these two compounds suggests that they cause
conformational changes to the enzyme complex, which lead to decreased binding of the
transition state inhibitor (Figure 7).
A
B
Figure 7. -secretase displacement assays.23
The displacement of a transition state analog, tritiated Merck A, by Sulindac Sulfide (A)
and R-flurbiprofen (B).
A proposed mechanism for this action was proposed by Hyman et al, who found
that the NSAIDs affect the conformation of PS-1, which leads to altered APP-PS1
conformation. The distance between the N-terminus and C-terminus was found to be
increased after the addition of s-ibuprofen, indomethacin, or flurbiprofen. (Figure 7) The
addition of these drugs causes a decrease in A42 and an increase in the less
amyloidogenic A3824.
17
A)
B)
C)
Figure 7: Structures of s-ibuprofen (A), indomethacin (B) flurbiprofen (C).24
Inhibition of secretase via the ATP Binding Site
Another approach to selectively inhibit -secretase enzymatic cleavage of APP is
by blocking the ATP binding domain. Wolfe et al. determined that production of Aand
AICD by -secretase cleavage of APP was dose-dependent on ATP concentrations. The
incubation of 1uM C100Flag (an APP based substrate), purified -secretase, and different
concentrations of ATP produced AICD-Flag, a fragment analogous to AICD, which is
produced in the normal pathway. As the concentration of ATP increases, the amount
AICD was found to increases (Figure 8). Using the ELISA technique with anti-A
antibodies, it was determined that as the ATP concentration increased from 1mM to
5mM, a 1.75 fold increase in A occurred.
18
Figure 8: ATP increases the hydrolysis of APP-based substrate.25
The group next sought to determine whether ATP concentration had an effect on
the production of a Notch substrate. Wolfe et al. found that increasing the concentration
of ATP did not increase the production of Notch fragments. This critical discovery led
the researchers to believe -secretase cleavage of APP could be selectively inhibited
without affecting the cleavage of other membrane targets, which was a problematic with
active site inhibition of -secretase.
The next step was to determine how ATP was responsible for -secretase activity.
The high energy released upon the cleavage of ATP’s terminal phosphate group is the
source of energy for many enzyme reactions. To see if -secretase requires cleaving ATP
into ADP or AMP, the enzyme was incubated with ATP in the presence of and in the
absence of an APP-based substrate. Following incubation, the amounts of ADP and
AMP were measured and it was found that increased hydrolysis did not occur in the
sample incubated with the substrate (Figure 9). This suggests that ATP hydrolysis is not
required for the activity of -secretase25.
19
Figure 9: -secretase does not require ATP hydrolysis.25
Lanes 1-5 show fragments of ATP that have been hydrolyzed by phosphotase to form
ADP and AMP.
Samples 6-10 were incubated with ATP, and -secretase. Upon electrophoresis, it was
shown that no hydrolysis occurred.
Samples 21-25 were incubated with ATP, -secretase, and an APP-like substrate. Upon
electrophoresis, it was shown that no hydrolysis of ATP occurred.
Contributing further evidence for this hypothesis was a study that found a 1mM
concentration of ATPS, a nonhydrolyzable ATP analog, increased production of A25.
This meant that merely the binding of ATP is necessary for -secretase cleavage. The
researchers were unable to find the exact effect that ATP has on the protein, however
they suggest that nucleotide binding causes a conformational change that allows the
protein to recognize APP.
Wolfe’s research group also investigated potential ligands for the inhibition of
APP cleavage. They found that tyrosine kinase inhibitors are potentially potent
therapeutics because they bind to ATP-binding sites and block the cleavage of an APPbased substrate. Compound 1367, one of the tyrosine kinase inhibitors, was also found to
stimulate the cleavage of a Notch-like substrate25.
20
Figure 10: Compound 1367 inhibits APP cleavage and induces Notch cleavage.25
At concentrations higher than 30m, Compound 1367 was found to be a potent inhibitor
of -secretase cleavage of an APP-like substrate, AICD-FLAG. Further studies showed
that 1367 actually increased Notch cleavage (NICD-Flag)
This approach shows much promise because of its ability to limit the production
of A peptides without inhibiting the cleavage of Notch, and in fact stimulating its
production.
CONCLUSION
The wealth of knowledge concerning Alzheimer’s disease is rapidly increasing
through the use of many biochemical techniques that aim at determining the root causes
of this debilitative neurological disorder. From Alois Alzheimer’s detection of abnormal
protein deposits in brain slides, both the -amyloid plaques and neurofibrillary tangles
have been researched extensively in the hopes of finding cures to halt their progressive
debilitating effects.
Aprotein fragments accumulate in intercellular spaces and cause neuronal death.
These fragments are created through the action of a family of proteases termed secretases.
While their activity produces a natural product, p3, the pathological causes of AD are
traced to the incorrect cleavage of the amyloid precursor protein by -secretase. Through
21
many well designed and well thought out experiments, it was found that -secretase is a
mulitpass transmembrane aspartyl protease, which gave further insight into the
mechanism for A production. Understanding the biochemical mechanisms allows
researchers to create therapeutic agents that could halt -secretase activity, and thus the
progression of AD. Currently, two major approaches are in clinical trials to test their
efficacy towards halting A 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 -secretase contains
an ATP binding domain. By blocking this site, it was found that the production of
Aproteins can be halted without stopping other important biological processes of secretase, including Notch cleavage.
The secondary cause of AD, one that 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 stabilizes 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
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 the wealth of knowledge concerning AD continues to be amassed the
possibility for creating newer and more effective drugs is increased. Significant findings
22
concerning the inheritability factors are also being researched. While the largest
contributing factor to developing AD is increasing age, there are several inheritable risk
factors that increase the risk for developing AD. These too are being researched in order
to tailor specific drugs and treatments for these problems.
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