1. Jonathon Burke
Cm11jpb@leeds.ac.uk
200604685
Amyloid diseases: Is there light at the end of the
tunnel?
Abstract
Alzheimer’s disease is an ever-prevalent disease, effecting millions of people
globally. In 1907 Alios Alzheimer hypothesized that amyloids play a key role in the
development of Alzheimer’s via the amyloid cascade theory. Since then researchers
have looked to examine and provide statistically significant data to support this
hypothesis. Although there is disagreement in the exact mechanism of impact,
amyloid-beta is thought to be key in Alzheimer pathology. These various mechanisms
will be assessed to provide an understanding to how Alzheimer’s and amyloids are
intrinsically linked. From there the question ‘is there light at the end of the tunnel?’
will be answered by looking at current developments in early detection and treatments
in current research.

2. Introduction
The impact of Alzheimer’s disease is felt not only in developed countries, but also the
entire globe. There are 830’000 people suffering with Alzheimer’s in the UK alone,
which has a cost of £23 billion (27)
. It is therefore clear why a fast and effective
treatment for Alzheimer’s disease is a priority for many drug companies. To
understand the treatments and future research, we will look at Alzheimer’s and the
impact of beta-amyloids in the disease. From there we will look into the different
approaches taken by researchers into effective treatments: from fast diagnosis to
ultimately finding a cure. (26,27)
The effects of Alzheimer’s spreads past the memory loss generally associated with the
disease. Cognitive functions that a healthy human takes for granted are affected at
different levels depending on the patient. The degenerative disease impacts all visual
and motor spatial and language skills. This over the course of the disease causes great
distress to patients and family members, as not only is memory loss prevalent, but
basic day-to-day skills are progressively lost. (3,5,7)
Advancing age, genetics and environmental risks are all major factors that impact on
the development of Alzheimer’s disease. A.B. Graves et al, state that the major factor
in development of Alzheimer’s is age. Studies suggest rates of 1-2% for 65-74 age
group with these rates doubling every 5 years. This increases to 25% in 85 and over.
There is conflicting data about the environmental impacts on Alzheimer’s
development. It has been postulated that lower education levels and a propensity for
depression can have an impact on Alzheimer’s development, although not concurrent
in studies. Smoking, age of mother at birth, and certain health conditions are also
believed to have an impact. It is difficult to truly assess the environmental impacts on
the development of Alzheimer’s disease and therefor apart from living a healthy life,
unlikely to deem credible impact on the treatment of Alzheimer’s. We can, take clear
data from this aging population, which will benefit current and future Alzheimer’s
research and treatment development. By doing this we can hope to learn from the
effects of age on development of Alzheimer’s and therefore look to limit certain
tributary steps that age effects. (3,6,7,10,13)
There has been considerable research into Alzheimer’s disease, with a common factor
pointing to the impact of Amyloid’s in the development of AD. To consider if there
truly is “light at the end of the tunnel’, it is beneficial to first look at amyloid
pathology and its impact on AD. From there it is possible to consider how this link
can be used to detect the onset of Alzheimer’s disease through early detection
methods. Along with early detection mechanisms, information into the links between
Ab and Alzheimer’s disease is leading to promising treatments, of which we will
assess some of the current developments.

3. Amyloid-b pathology and Alzheimer’s disease
Amyloidosis is the misfolding and accumulation of extracellular proteins that causes a
specific disease. There are 27 human proteins with the ability to be amyloidogenic.
There is a lot of attention paid to amyloids, as their aggregation is associated with a
variety of organ illnesses. Karen E et al (10)
“Amyloid is an abnormal extracellular
fibrillar protein deposit in tissues”. A variety of different proteins allow varied
deposition and therefore attribute to many syndromes associated to respective fibril
protein precursor. In general terms, amyloid formation occurs when a peptide doesn’t
acquire its functional fold allowing the ordered formation of fibrils. The likelihood for
fibril formation is increased with certain in vivo factors: increase in protein
concentration, unstable amyloidogenic proteins protein cleavage and age. Although
there is disparity in suggested mechanism’s for Beta-amyloid pathology in
Alzheimer’s disease, it is clear that is has an impact on disease development. (6,10,13,23)
Beta amyloids are made up of 40 and 42 amyloid-b peptides (Ab 40. Ab42). B and Y
secreteases allow secretion of the Ab protein precursor (APP), it does this through the
B-site APP-cleaving enzyme (BACE-1). This cleavage generates an APPb (sAPPb)
and a membrane-bound C-Terminal fragment of APP (CTFb). C-terminal APP is
then cleaved by Y secretease forming other lengths of APP (37,38, 43). Further Ab is
generated by the enzymes isomerase, glutaminylcyclase and aminopeptidase. (6,10,13)
Figure 1, APP processing to generate Amyloid-beta (amyloidogenic and non-
amyloidogenic pathways)(13)

4. In 1907 Alios Alzheimer ‘s examination of AD brains found an accumulation of b
amyloid and hyperphosphorylated tau protein. These were seen to form plaques and
neurofibrillary tangles, leading to the amyloid cascade hypothesis. (10)
Figure 2, The amyloid cascade hypothesis. (10)
An increase in Ab is thought to cause a variety of neurotoxic changes: oxidative
stress, fibril deposition, tau protein aggregation and inflammatory responses. (Future
science editorial). Accumulation of b-amyloid in the brain parenchyma is
hypothesized to be a crucial step in the onset of AD. Dominate mutations of three
genes; presenilin1 (PSEN1), presenilin2 (PSEN2) and amyloid precursor protein
(APP) allow this accumulation to occur. Although it is clear the relationship between
cognitive decline and Ab deposition is not linear, Ab-derived diffusible ligands and
soluble oligomers are proposed to account for neurotoxicity. (10)
There are many ongoing studies into this hypothesis, but so far there is increasing
evidence to show that the cognitive decline present in AD is caused by the
accumulation of soluble oligmeric assemblies of Ab. Insoluble Ab plaques are
thought to also effect cognitive function but data is not always consistent with
neuronal degeneration. (13)
Since hypothesizing the amyloid cascade theory, further research into the relationship
between Ab and Alzheimer’s disease has been conducted. Using modern techniques,
there have been significant developments into the understanding of this relationship.
Although there is ongoing debate into the exact relationship between, it is important
to review the relationship’s outlined in modern scientific journals. These studies offer
some insight and support for the potential mechanism of AD development via
amyloid-beta deposition.

5. Synaptic health by signal transmission among neurons (LTP) is reduced in AD
patients by accumulation of Ab. As there is a clear link between synaptotoxicity and
memory loss in AD, it is thought that Ab may inhibit LTP by oligomer-targeted
receptors at the synaptic plasma membrane. Snyder et al. proposes that endocytosis of
N-methyl-D-aspartate (NMDA) receptors causes disturbance in calcium influx. There
is interaction with receptor for advanced gylcation end (RAGE) products receptor and
insulin receptor, which induces oxidative stress. Build up of reactive oxygen species
(hydroxyl radical, superoxide radical etc.) leading to oxidative stress is shown to
cause synaptotoxicity leading to neuronal death by Ab oligomer. A strong correlation
is reported between oxidative damage levels and dementia. Varying mechanisms are
proposed, “Klein and colleagues proposed that ADDLs induce LTP accompanied with
oxidative damage”. It is understood that superoxide dismutase (SOD) converts
superoxide radicals to hydrogen peroxide. The amount of SOD in AD brain was
larger than in normal brains. K. Murakami et al found that, in mice with both AD and
raised SOD levels, “Ab oligomerization associated with memory loss and synaptic
loss was worsened”. This implies that there is “stimulation of the amyloidogenic
pathway by cytoplasmic superoxide radicals”. (13)
There are continual studies into establishing the link between b-Amyloid and
Alzheimer’s. This is because the exact method off effect and therefore positive
correlations are largely hypothesized. Villemage et al (2012) and Ellis et al (2013)
show an association between amyloid-b positivity and decline in episodic memory (18
&36 months) in clinically diagnosed mild cognitive impairment (MCI) patients. The
cognitive decline in these otherwise healthy patients shows that Alzheimer’s related
neurodegeneration could be detected with pre clinical diagnosis. To further this
research, Yen Ying Lim et al (2014) proposed “all aspects of cognitive function
would remain stable in healthy older adults and individuals with MCI who were Ab
negative”. Healthy older adults showed no change in cognitive function, however
individuals with MCI showed improvement in cognitive function. Suggesting that
patients diagnosed with MCI but not Ab positive are suffering with neurological
problems other than Alzheimer’s. (11,13)
Yen Ying Lim et al (2014) also hypothesized that “in healthy older adults, individuals
with MCI and individuals with Alzheimer’s disease, Ab- positivity would be
associated with decline in memory over 36 months”. This showed that, in amyloid-b
positive healthy older adults, verbal and visual episodic memory showed a moderate
decline over 36 months compare to amyloid-b negative healthy older adults. MCI
amyloid-b positive patients showed a larger rate of decline in verbal and visual
episodic memory when compared to Ab negative healthy older patients. Language,
attention and visuospatial functions also declined in MCI Ab- positive patients.
Patients with Alzheimer’s who are amyloid-b positive exhibit large cognitive function
decline when compared to amyloid-b negative healthy older adults. The greatest area
of decline was language and visuospatial function. (13)

6. Jack et al (2010,2013) proposed the pathophysiological model of Alzheimer’s disease
that suggests amyloid-b accumulation slows after meeting the clinical criteria for
Alzheimer’s. This means the temporal element must be considered when looking
amyloid-b levels in younger adults. Yen Ying Lim et al (2014) show that cognitive
decline in Ab positive Alzheimer’s patients does not plateau, but continues to decline
at a similar rate to non-MCI Ab positive patients. This continual memory decline,
coupled with the increase in non-memory decline, is indicative of even the earliest
stages of Alzheimer’s disease. This suggests that assessing non-memory functions in
Alzheimer’s disease could be beneficial for the detection of early disease
development. (11,13,17)
Yen Ying Lim et al (2014) also show that there is a relationship between the amount
of amyloid-b positivity and Alzheimer’s. Quantifying the relationship between Ab
and Alzheimer’s development is fundamental in providing significant links. It is
proposed that an SUV ratio of >1.90 is optimal for diagnosis. Therefore, in patients
who are not currently clinically diagnosable as having Alzheimer’s, but have an SUV
ratio of >1.90 have a higher positive predicted rate of Alzheimer’s progression. It also
suggests a relationship between the amount of Ab present and cognitive decline
associated with early onset Alzheimer’s. By providing doctors with a way of
assessing the risk a patient has of Alzheimer’s when not showing signs of MCI,
preemptive steps to actively combat the disease could be taken. (11)
It is clear that Ab pathology and Alzheimer’s disease are intrinsically linked. Poor
clearance of amyloid-b precursor protein could be critical in the early development of
AD, as it leads to Ab accumulation and plaque formation long before clinical
diagnosis. Frontal and parietal midline structures and the default mode network
(DMN) are areas of high metabolic activity and intrinsic functional connectivity. The
DMN is linked to deposition of plaques due to overlap in average deposition regions
with the DMN. This overlap has lead to the theory that Ab neurodegeneration in
Alzheimer’s disease “occurs along network boundaries, spreading to functionally
connected areas rather than to spatially contiguous but less connected neighbours”.
This implies two relationships: reduction in intrinsic activity and connectivity linked
to Ab, and a positive relationship between high connectivity and high Ab pathology.
Nicholas Myers et al (2014) found that, in early onset Alzheimer’s disease, there were
two effects of PIB-uptake on connectivity. The highest areas of connectivity showed
the highest level of plaque buildup on a globular network level. On a local network
level, “plaques are negatively liked with connectivity”. The observed characteristics
of early onset AD, that primary sensory and sensorimotor regions are largely
unaffected was supported by the observed plaque distribution in heteromodal
networks. It was observed that patients with early onset AD exhibited significant level
of Ab plaque formation, with the posterior DMN most affected, confirming a
relationship between Ab plaque load and connectivity. This relationship supports the
hypothesized statement that amyloid-b pathology has a negative impact on intrinsic
connectivity, but was also seen to go past the DMN to other heteromodal networks. It
is therefore possible to suggest that in the early stages of Alzheimer’s disease, Ab-
pathology is linked to increased connectivity. In the later stages of AD amyloid-b
pathology is linked to decreased connectivity, but it must be remembered that some
areas of the brain will be affected at different rates to others. (3,14,16,20)

7. The effect of amyloid-beta on Alzheimer’s is seen in a variety of areas. A decrease in
synaptic activity by neuronal decay leads to an overall decrease in memory. Evidence
to show this is linked to Ab oligomer accumulation suggests that amyloidosis is
impactful in MCI related to Alzheimer’s disease. This synaptic decay is seen to be
more prominent in areas of high metabolic activity such as the DMN. This suggests
that areas of higher intrinsic functional connectivity are prone to greater levels of
synaptoxicity and therefore exhibit the strongest impact of Ab aggregation. It can be
seen that an overall increase in the amount of amyloid-beta accumulation correlates
with the onset of AD, and that the amount of Ab present is proportional to the
development of observed Alzheimer’s disease. This accumulation is seen to effect
both memory and on memory areas of cognitive function, with visuospatial and
attention functions also effected. Although the above studies present the effect of
amyloid deposition with different mechanisms, they all show the same underlining
problem; that amyloid deposition impacts on brain function in AD patients. The
variety of hypotheses open up many avenues for future research into both the stated
relationship, and to future treatments for Alzheimer’s disease. (1,3,14,16,20)
Early detection
In a clinical setting, it is regularly observed that a patient is exhibiting some, but not
all signs of Alzheimer’s development, before a full clinical diagnosis can be achieved.
It is often the case that the impact of Alzheimer’s is too far onset by the time full
clinical diagnosis is accomplished. For there to be ‘light at the end of the tunnel’, a
combination of approaches to tackling Alzheimer’s disease could be taken. If it is
possible to assess and diagnose AD development prior to current clinical diagnosis,
more time can be given to patient and doctor to effectively treat the disease. Studies
into the development of the disease and identification methods offer potential into
possible steps for quick diagnosis.
It is important to assess any relationships between amyloid-b pathology and the
reduction in cerebral blood flow in Alzheimer’s patients. This is because rate of
cerebral blood flow and effects on locations within the brain, may have an impact on
future treatments that target Ab fibrils. There is also observed relationships between
rate of CBF and metabolic activity of the brain, indicating brain activity. Miklas
mattsson et al (2014) found that ‘brain amyloid-b load was associated with reduced
CBF in poro-parietal regions across all subjects”. CBF in Ab positive patients was
reduced when compared to Ab negative patients. It was also found that the effects of
Ab load differed between CBF and volume, suggesting “Ab has a stronger association
with brain function than with structure in mild disease stages, but larger associations
with structure in advanced stages”. Lowered CBF in temporo-parietal and frontal
regions in AD patients was found which supports Alsop et al (2010) findings. Miklas
mattsson et al (2014) observed “reduced CBF in several AD related brain regions
regardless of cognitive status”. This supports the hypothesis that Ab positive subjects
have Ad pathology, but also that MCI early and late have varying level of AD
pathology. The positive correlation between higher amyloid-b load and increased
CBF in several brain regions in AD patients was found. This increase in perfusion is
suggested to be a compensation for Ab neurotoxicity. The generally accepted
hypothesis that AD starts with Ab pathology in healthy adults, following a
progression of neurodegradation, reduced brain activity and clinical symptoms is
supported by Miklas mattson et al (2014). By dividing groups into Ab load and then

8. comparing within the diagnostic groups, they were able to determine a reduction in
CBF for early and late MCI and Alzheimer’s patients. From this it could be possible
to isolate Ab positive Alzheimer’s patients in people with varying cognitive decline.
(11,12,14,16)
Another consideration by Miklas mattson et al (2014) is the varying association
between Ab pathology, CBF and structural measurements. Ab load was associated to
reduced CBF, but a small/positive impact on grey matter volume. However, when
compared with Ab positive late MCI or Alzheimer’s patients, the effects of Ab on
structure were more significant. There were greater reductions in brain volume than
CBF, which support assessments of advanced stages of the disease. Negligible
differences in early MCI support the hypothesis that synaptic loss is a primary step in
Alzheimer’s disease development. Synaptic loss causes an overall reduction in brain
activity, which can be seen in a reduction of CBF. From Miklas mattsson et al (2014)
it is possible to postulate that early onset Alzheimer’s may be represented by a
reduction in CBF before grey matter reduction. This opens up the possibility for
doctors to diagnose high-risk patients based on CBF far sooner than if they were
assessing grey matter atrophy. The accumulation of amyloid-b is also considered an
early indicator of Alzheimer’s disease. Through combined use of PET and CSF
biomarkers, it is now possible to visualize fibrillar Ab plaques in the brain. 11
C-
pittsburgh compound B (PIB) is regularly used as it has been heavily studied,
showing detection of Ab fibrils with high accuracy. The use of PET with PIB has
shown high retention of the biomarker in AD brains, as well as MCI patients prior to
Alzheimer’s development. The use of other biomarkers is a key area of development
for AD diagnosis. 18
F-florbetapir and 11
C-PIB have shown promising associations,
and offer benefits over 11
C-PIB. 18
F amyloid tracers have the potential to be more
suitable for clinical usage, as they have a longer half-life, allowing greater distance
between cyclotron and hospital. They also require a shorter scan time (10 min)
compared to 11
C-PIB (60-90 min). (11,12,14,16)
Ruiqing Ni et al (2013) assessed the use of 3
H-PIB as a suitable biomarker. Using the
frontal cortex as a region with high amyloid and hippocampus with low amyloid load.
High and low affinity sites in the frontal cortex and hippocampus were observed in
AD patients, compared to only low affinity sites in normal patients. A common high
affinity binding site for PIB in AD brains were also observed. The ratios of high to
low in the frontal cortex was 6:1, hippocampus 3:1 and this has been attributed to
more high affinity sites in the frontal cortex. Tracer retention was observed in small
amounts of the control, which lends itself the effects of age. Although low affinity
sites aren’t imaged using current techniques, they could have an impact on Ab
aggregation and overall development of Ab pathology in the brain. From the findings,
Ruiqing Ni Et al (2013) propose a multi-binding site model (1,2 &3). When
considering early detection, it is important to make sure that all variables between
patients and AD models are considered. Nicholas Myers et al (2014) ‘analyzed the
within subject relationship between amyloid-b pathology and functional
connectivity”. By creating this model, future research can be carried out to further the
hypothesized model, and so allow a greater understanding between the links. If
supporting data is found, it could yield a strong boost to early detection and
quantization of the development of the disease in patients. It could also yield future
developments in biomarkers for early detection. (11,13,14,15)

9. By combining a greater understanding into the expected pathological development of
Ab aggregation in Alzheimer’s disease patients, with more effective tracers and
modern imagining techniques, there could be ‘light at then end of the tunnel’ for early
detection. It is feasible for researchers to be able to develop a clear early detection
system for the development of AD in patients exhibiting some cognitive impairment.
Treatments
For there to truly be ‘light at the end of the tunnel’, effective treatments for
Alzheimer’s disease are needed. Due to the high cost involved, pharmaceutical
companies at great risk undertake drug development. According to alzforum, there are
44 amyloid-related therapies listed. Of these 44, 12 are discontinued and 3 are
inactive. Although there is great risk involved at a drug failing, pharma companies
invest heavily due to the potentially lucrative business in successfully developing an
effective treatment.
Amyloid-b immunotherapy is researched as a potential treatment for AD. There are
currently 2 passive immunotherapy treatments at stage 3 of clinical trials:
Gantenerumab and Solanezumab. Although active immunization is successful in
lowering Ab oligomer levels, there are significant safety concerns associated with this
method. The removal of both pathological and non-pathological Ab is thought to be
the reason for this, and as the function non-pathological Ab is not fully understood, it
should be avoided in current techniques. Passive immunization, through the regular
administration of antibodies could therefore be an option for AD treatment. This
method allows the use of antibodies that work against specific conformations of Ab,
of which there are over 600 currently listed. Presuming that the antibodies can cross
the blood brain barrier, two mechanisms for the antibodies are suggested. Binding of
antibodies to Ab complex induces phagocytosis, and the antibodies prevent that
aggregation of Ab. The use of conformation specific antibodies to attack different
lengths of Ab is an option for treatment. Antibody A11 reacts with several types of
Ab but doesn’t recognize Ab fibrils. This is useful as it is binding to Ab intermediates,
which could allow active combating of Ab oligomers before fibril formation. Further
development of A11 to be an antibody for annular protofibrillar oligomer (aAPF)
extends the applications of A11. OC antibody has the opposite effect of A11; it
recognizes only amyloid-b fibrils. As previously stated, increased levels of fibrillar
Ab oligomers are found in the brains of AD patients, indication a clear use for OC
antibody. However no significant difference in prefibrillar Ab oligomer was found,
meaning the use of stage 1 A11 could be largely ineffective. There are, however,
raised levels of aDPF in the CBF pre-clinical diagnosis for AD. This opens up the use
of stage 2 A11 as a biomarker for aAPF. (3,5,13,26)
As it is known that Ab-42 ADDLs cause oxidative stress and synaptoxicity, the
formations of relevant antibodies could yield positive effects. Anti-ADDls antibody
(Nu-1) allows the discrimination between Alzheimer’s and non-Alzheimer’s brain.
Nu-1 has been shown to “significantly rescue Ab-42 induced LTP inhibition as well
as ROS”. Further development of NU-1 to combat localized ADDLs and so to inhibit
dendritic spine reduction has yielded further positive results. Globular Ab-42
oligomers have been shown to “inhibit spontaneous synaptic function”. The antibody
A-887755 has shown to only recognize globular Ab-42 oligomer and not monomer or
fibril plaque formations. This allowed induced synpatoxicity to be neutralized

10. allowing an improvement in novel object recognition. The use of A-887755 in passive
immunization was also found to improve overall cognitive function and increased
synaptic density. With the observed dangers in plaque removals, these antibodies
could offer a safe alternative to other AD treatments. Toxic conformers of Ab-42 are
thought to occur through an oxidation in a peptide in the oligomer. Although it is
thought that this oxidation can occur at various turns, oxidation at Met35 (turn 22,23)
forms toxic Ab-42. These toxic oligomers have observed synaptoxity and therefore
offer an option for treatment to negate their effect in AD. A developed antibody,
11A1, has shown the ability to recover neurotoxicity and inhibit cytotoxicity. 11A1
did this by detecting the related toxic Ab-42 oligomers stopping aggregation and
neurotoxicity. It has also been observed that 11A1 also recognized intracellular Ab,
this staining occurred in both AD and non-AD brains. The isolation of intracellular
Ab in non-AD brains by 11A11 has lead to the possibility of pre AD detection. NU-1
also showed intracellular Ab staining. Although it is unclear how deposition of
intracellular Ab-42 occurs, its potential as antibody target should not be ignored.
(3,5,13,26)
As well as environmental factors, genetic variation is a risk factor for the onset of AD.
Variation in the APOE gene increase disease risk as normally functioning APOE
helps in the formation of HDls, which aid in the degradation of soluble Ab. Agonists
of APOE receptors “also act on macrophages and microglia” to form alternative
active sites and promote phagocytosis. It is fair to assume that expression of these
agonists could aid Ab clearance and therefore alleviate AD risk. Paige E. Cramer et al
(2014) identified that RXR agonist would allow APOE expression, which, in turn,
would aid Ab clearance and promote phagocytosis. Bexarotene (RXR agonist)
lowered Ab levels in the CBF within 6 hours and offered a 25% reduction at 24 hours.
Further reduction was seen over a 70-hour period, with a return to normal levels after
84 hours. With continual dosage, a 30% reduction in soluble Ab levels and 40% in
insoluble Ab was observed. Similar results were expressed in later stages of AD,
suggesting that bexarotene works across all stages of AD. As was previously
suggested, soluble Ab deposition has a negative effect on MCI through impairment o
synaptic function. Beraxotene exhibited restoration of cognitive function, memory
and improvements to impaired olfactory systems. (1,4,6,9,18)
A problem with delivering treatments for Alzheimer’s is getting the drug across the
blood brain barrier in the correct dose. Nanoparticles offer an interesting area of
research for drug developers to combat this issue. They offer the possibility to not
only deliver a range of drugs, but also have the ability to provide the drug for a
sustained period of time. Juliana B. Hoppe et al (2013) approach the use of
nanoparticles with curcumain, which is understood to have neuroprotective effects.
The use of lipid core-nanocapsules coated in polysorbate 80 to enhance the brain
delivery of the drug. An appeal to nanoparticles is there ability to provide a
therapeutic dose to the target with decreased amount of administered drug. The dose
necessary for nanoencapsulated was 20fold lower than that of free curcumin.
Exhibiting a higher concentration (2.5 times) in cerebral tissue over free drug and a
longer mean residence time (14 times) than that of the free drug. The ability to
provide a specific drug, in smaller administered doses for a longer duration, could
open up possibilities past the administration of curcumin. LNC’s also seem to avoid
side effects over a 28 day treatment, due to being non-toxic and reduced dosage. Both
nanoencapsulated and free curcumin were seen to be active in preventing

11. inflammation, tau hyperphosphorylation, behavioral impairments (seen to be
associated with Ab aggregation) and signal disturbances. It is hypothesized that the
hippocampal region is crucial in AD patients, and therefore synaptic loss correlates to
cognitive impairment. It was observed that curcumin, in both forms, acted against Ab
related synaptocicity due to raised synaptophysin levels. Ab is also thought to trigger
microglial cells, which are active in neurodegeneration by phagocytizing after
synaptic rewiring and release of proinflamatory cytokines. Both forms of Curcumin
were seen to decrease microglial activation, but only LNC reduced levels of cytokines
in the hippocampus. This is hypothesized to be caused by LNC’s greater bio-
distribution throughout the brain. BDNF/neurotrophins are noted to decrease with an
increase in proinflammatory chemicals. Curcumin was seen to rescue and then up-
regulate BDNF levels in the hippocampus, which leads some way to explaining the
cognitive improvements exhibited. BDNF acts through the AKt pathway to maintain
neuronal health; Ab in AD brains directly impacts this. One such component of AKT
pathway is GSK-3b, which has roles in tau phosphorylation and cytokine production.
Treatment with curcumin stabilized phosphorylation and inhibits GSK-3b. (8,17,24,25,26)
Tau protein phosphorylation, and neurodegeneration by Ab is key in AD pathology.
Hyperphosporylation of the tau protein causes reduction in microtubule affinity.
Detachment of microtubules disrupts axon transport resulting in synaptic
degeneration. There is one treatment for tau phosphorylation in phase 3 clinical trial;
TRx0237. It is a small molecule treatment that is already approved for treatment of
malaria and methemoglobinemia. (8,13,17,24,25,26)
Conclusions
With Alzheimer’s having a large, cross-population impact, both researchers and
pharmaceutical companies are searching for the ‘light at the end of the tunnel’.
Research is continual into understanding the link between Alzheimer’s disease and
amyloid-beta aggregation. Although there is not currently a unanimously agreed
single mechanism for the link between the two, it is possible that there are a number
of different pathways that Alzheimer’s disease goes down in relation to Ab
accumulation. By taking a step back and assessing all these avenues, there may be a
possibility of finding common ground between all these hypotheses. The chance of
decreasing diagnosis time offers a unique opportunity to the treatment of Alzheimer’s.
By isolating a patient as being high risk/early onset then a patient is open to treatment
a lot earlier. This may allow more effective therapy and potential to overcome the
disease before lasting synaptic damage is done. A major risk with late detection is that
brain atrophy is past the point of acceptable recovery, therefore emphasis on early
detection is key to there being ‘light at the end of the tunnel’. Combining this early
detection with treatments in development could be a fruitful path for overall
treatment. Immunotherapy and Ab clearance offer future generations a real chance of
overcoming Alzheimer’s. This review set out to see if there was truly ‘light at the end
of the tunnel’; with current research and future developments in both techniques and
understanding, science offers a real opportunity for this life changing disease to be
beaten.

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