Alzheimer’s disease is a neurodegenerative disease which
“destroys neurons, leading to cognitive, memory and behavior impairments”
(Stutzmann 1) and is a major and growing problem in the United States. While
much research is being performed to identify a cure or early prevention method
for this disease, both have remained out of reach. However, recent work on
Apolipoprotein E (APOE), a gene which is linked to the development of
Alzheimer’s disease, detailed in the article “Could the ‘Alzheimer’s Gene’
Finally Become a Drug Target?” by Esther Landhuis, may be the key to early
prevention, as this blog will explore, through the use of.
While discovered over
25 years ago, the APOE gene had remained largely a mystery at to exactly how
the gene begins to cause dementia, although people with a mutation of this
gene, specifically the APOE E4 version, are “four to 15 times more likely to
develop Alzheimer’s” (Landhuis) than those without it, a staggering statistic
that had many scientists interested in developing treatments for the disease,
although most have been unsuccessful. Another protein which is associated with
APOE, Amyloid Beta (AB), is able to “accrue in the brain for years, disrupting
nerve connections essential for thinking and memory” (Landhuis) leading to
Dementia. In much the same way as APOE, many resources were poured into
developing a drug-therapy focusing on the destruction of these Amyloid Beta
proteins, with no success being found.
While the link has
not been completely discovered, one important finding thus far has been that
patients with a mutation in the APOE gene developed much greater levels of AB
in their brains than patients with a normally functioning APOE gene, and that
AB proteins “clumped more readily” (Landhuis) in the presence of APOE proteins,
specifically the APOE E4 protein, than trials in which no APOE proteins were
present. This leads to the conclusion that APOE may be directly linked to AB
buildup in the brain, and that controlling APOE levels may help decrease the AB
buildup and thus lessen the severity or some of the symptoms of Alzheimer’s,
specifically relating to memory loss. In much the same way, according to the
article “Early calcium dysregulation in Alzheimer’s disease: setting the stage
for synaptic dysfunction” by Grace E. Stutzmann, who spoke at Loyola University
Chicago, another link to the development of these AB buildups and APOE protein
expression could be in the disruption of neuronal calcium signaling, as noted
“a subsequent pathological cascade may develop between increased calcium levels
and AB depositions” (Stutzmann 3) in patients with Alzheimer’s disease. In this
way, the two articles are directly linked, as both irregular calcium signaling
and APOE expression are related to the AB buildups in the brain. While, as
stated, researchers found mixed results with a drug therapy targeting APOE
expression, it is possible that a dual-drug therapy, one focusing on APOE
expression and the other on calcium signaling may yield greater results in
patient trials than each therapy individually. As well, the article states
“ApoE4 expression increases intracellular calcium levels” (3), which is noted
causes disruptions in calcium signaling, further demonstrating the direct
association between calcium signaling and APOE expression.
(BrightFocus
Foundation)
While the connection between APOE and calcium signaling is
displayed through AB buildup in the brain, another connection, in the form of
Tau proteins, is also demonstrated. Tau is a protein which “forms so-called
‘tangles’ within the nerve cells” (Landuis), a hallmark characteristic of
Alzheimer’s disease. While these tangles were assumed to be the result of AB
entering the brain, Dr. David Holtzman proved otherwise, as studies he
conducted at Washington University “showed tangle production had nothing to do
with amyloid and everything to do with APOE”
(Landuis), thus showing, as was the case with AB, APOE was directly related to
Tau, which was a contributor to the development of Alzheimer’s disease. If APOE
was able to be controlled, or out-right lacked, in the human brain, then the
progression of both AB and Tau would not occur, thereby delaying or stopping
some of the major symptoms of Alzheimer’s disease. In fact, in a separate study
done by Dr. Holtzman, this was directly observed, as “if mice were genetically
rigged to lack ApoE, their brains looked fine” (Landuis). Tau proteins in the
brain are also associated with calcium signaling, as the article by Stutzmann
notes a “relationship may exist between calcium signaling and tau pathology”
(Stutzmann 3). The article does not focus heavily on the tau proteins in their
relation to calcium signaling, but based on the connections between calcium
signaling, AB buildup, and APOE proteins, it is clear that some connection must
exist between calcium signaling and Tau proteins. As before, targeting of both
APOE proteins and calcium signaling, instead of treating each individually, may
yield better results in the treatment of Alzheimer’s than what has previously
been shown. In addition, it should be noted that problems associated with both
calcium signaling and APOE are “present throughout the organism’s lifetime”
(Stutzmann 3), meaning that screening for these symptoms could be done years
before the symptoms of Alzheimer’s would even to begin to appear in a patient,
giving doctors and patients alike more time to develop a prevention plan before
the disease has progressed too far, where mitigation of the symptoms is the
only option available for patients. In the case of APOE, as Dr. Holtzman puts
it, “if you lower ApoE early in life, it could prevent or slow amyloid
deposition” (Landuis), which would in turn could help lessen the severity of
the disease or knock out one of its symptoms entirely.
(Eli Lilly’s Experimental Alzheimer’s Drug Fails in Large Trial)
(Alzheimer’s Association)
While calcium signaling and APOE proteins seem like
promising indicators or causes of Alzheimer’s, much work is still needing to be
done to effectively treat these symptoms, particularly in regard to APOE
proteins. One function of lowering APOE proteins, around the time of where
cognitive impairments begin to arise, is to lower the inflammation in the
brain. However, much disagreement has come from this, as some argue the
inflammation early on may be beneficial and it is only in later stages that the
inflammation becomes detrimental. This becomes a problem then, as when exactly
does the inflammation go from being helpful to problematic, so that drugs to
lower APOE can be used effectively. This is one area which must be decided upon
before drug-therapy will be able to be introduced to the wide scale market. In
addition, APOE proteins do perform other functions in the body. In particular,
they help “carry cholesterol and other fats through the bloodstream” (Landius),
so people who lack APOE proteins tend to have problems controlling their
cholesterol levels. This may pose a problem to patients who already have
cardiovascular related issues, so this will as well need to be resolved. The best-case
scenario for a treatment would be one which would “lower ApoE in the brain, but
not in the blood” (Landius), which again will require time to achieve before a
drug is available. Although these detriments are apparent, the successes of
both of these papers are still very impressive and are note-worthy.
The two articles by
Esther Landius and Beth Stutzmann displayed a lot of overlap in the area of
prevention of Alzheimer’s disease, with irregularities in calcium signaling and
APOE expression becoming very promising pre-cursor for major causes of the
disease, such as buildup of Amyloid Beta and expression of Tau proteins. With
further research, these may prove to be invaluable in the prevention of
Alzheimer’s, which may in turn save many lives. Just like how the calm serves
to signal people of the impending storm, the detection of irregularities in
calcium signaling and the APOE proteins may signal patients of the impending
storm that is Alzheimer’s and maybe, will hopefully allow them time of get out
of the way.
Works Cited:
Landhuis, Esther. “Could the
‘Alzheimer's Gene’ Finally Become a Drug Target?” Scientific American, 11 Oct. 2017, www.scientificamerican.com/article/could-the-ldquo-alzheimer-rsquo-s gene-rdquo-finally-become-a-drug-target/.
Retrieved 5 Dec. 2017 from www.ScientificAmerica.com
Stutzmann
G., Charkroborty S. (2011) Early calcium dysregulation in Alzheimer’s disease: setting the stage for synaptic
dysfunction. Science China 54: 1-11, Aug.
2011.doi:10.1007/s11427-011-4205-7
“Normal vs. Alzheimer's
Disease Brain.” (Figure 1) BrightFocus Foundation, www.brightfocus.org/alzheimers/infographic/amyloid-plaques-and-neurofibrillary-tangles.
“Alzheimer's Brain.” (Figure
2) Alzheimer's Association, www.alz.org/braintour/healthy_vs_alzheimers.asp.
