Cellular, Molecular, and Genetic Basis of Alzheimer’s Disease

Alzheimer’s Disease, like many neurological conditions, is not well understood. Researchers are making great strides in understanding the mechanisms by which AD destroys neurons but are, as of yet, still without a cure. What follows is a brief summary of the general research available on AD as well as a description of the progression of Alzheimer’s symptomatology. Following my post is an excellent animation produced by three prominent groups: Internationale Stichting Alzheimer Onderzoek, Alzheimer Forschung Initiative, and La Ligue Européenne Contre la Maladie d’Alzheimer.

Understanding Alzheimer’s Disease requires analysis at the genetic, molecular, and cellular level. In my experience it is beneficial, in terms of understanding the material, to start with those protein structures that exist at the cellular level, followed by an analysis of the molecular structure, and conclude with the role our genetics may play in regulation and production of these proteins.

Tau Protein

(Image from: La Ligue Européenne Contre la Maladie d’Alzheimer)

Cellular. Our brains communicate via an intricate network of nerves in the form of action potentials which are propagated down axons via pathways of microtubules. These are supported structurally by Tau proteins. When the body produces faulty Tau proteins they are released from the microtubules and congregate together. These microscopic protein clumps prove fatal to the neuron. The axons of the neuron fold in on themselves and wrap around the soma forming what is called neurofibulary tangles (NFT). NFT is considered one of the two primary malfunctions within a normally functioning brain required for the presence of Alzheimer’s disease.

The other malfunction involves the improper cleaving of a protein from a cell which congregate in long tubes. These tubes form tangled web like structures called Senile Plaque. In order to understand senile plaque we must take a look at the molecular structure and mechanisms by which cleaving is malfunctioning.

Senile Plaque

(Image from: La Ligue Européenne Contre la Maladie d’Alzheimer)

Molecular. Normal cells produce a protein called APP which is attached to the outer membrane of the cell. α-Secretase cleaves the APP and releases Amyloid-beta into the body and it is dissolved. In a malfunctioning system β-secretase cleaves the APP protein in the incorrect position followed by a second cleaving by γ-secretase. This Aβ molecule congregates into large microtubules and forms fibrils which are not soluble. These are known as Senile Plaque. The presence of both NFT and Senile Plaque are what researchers believe leads to Alzheimer’s disease.

Genetic. The current understanding of the genetic connection to AD is small. Only a small percent (around 2-3%) are the result of genetics, however several genes have been identified. The Apolipoprotein E (APOE) has been identified as a possible contributor. It is made up of several codons including e2, e3, and e4. Late onset Alzheimer’s disease has been connected to the presence of more e4 codons and early onset Alzheimer’s disease seems to be present when more e3/e4 codons are present. No one is genetically immune to Alzheimer’s disease. Additionally Presenilin 1 and 2 have been identified with the improper cleaving of APP by γ-secretase.

Treatment. Treatement of Alzheimer’s disease could target any of the protein structures listed above including Tau Neurofibulary Tangles or Senile Plaque. In addition pharmacology could target the presence of β-secretase or α-secretase. Gene therapy is also a possibility but because so few AD cases are a direct result of genes it is unlikely gene therapy alone would be sufficient in preventing the disease.
 Bibliography and for more information:

Annaert, W., & De Strooper, B. (2002). A cell biological perspective on Alzheimer’s disease. Annual Review of Cell and Developmental Biology, 18, 25–51. doi:10.1146/annurev.cellbio.18.020402.142302

Bali, J., Halima, S. Ben, Felmy, B., Goodger, Z., Zurbriggen, S., & Rajendran, L. (2010). Cellular basis of Alzheimer’s disease. Annals of Indian Academy of Neurology, 13(Suppl 2), S89–93. doi:10.4103/0972-2327.74251

Braak, H., & Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathologica, 82(4), 239–259. doi:10.1007/BF00308809

Gitlin, L. N., Marx, K. A., Stanley, I. H., Hansen, B. R., & Van Haitsma, K. S. (2014). Assessing neuropsychiatric symptoms in people with dementia: a systematic review of measures. International Psychogeriatrics / IPA, 26(11), 1805–48. doi:10.1017/S1041610214001537

McGhee, D. J. M., Ritchie, C. W., Thompson, P. A., Wright, D. E., Zajicek, J. P., & Counsell, C. E. (2014). A Systematic Review of Biomarkers for Disease Progression in Alzheimer’s Disease. PLoS ONE, 9(2), 1–9. Retrieved from 10.1371/journal.pone.0088854

Selkoe, D. J. (2001). Alzheimer’s disease: genes, proteins, and therapy. Physiological Reviews, 81(2), 741–66. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11274343

St George-Hyslop, P. H., & Petit, A. (2005). Molecular biology and genetics of Alzheimer’s disease. Comptes Rendus Biologies, 328(2), 119–30. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15770998

Weiner, M. W., Veitch, D. P., Aisen, P. S., Beckett, L. A., Cairns, N. J., Green, R. C., … Trojanowski, J. Q. (2013). The Alzheimer’s Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimer’s & Dementia : The Journal of the Alzheimer’s Association, 9(5), e111–94. doi:10.1016/j.jalz.2013.05.1769

Winner, B., Kohl, Z., & Gage, F. H. (2011). Neurodegenerative disease and adult neurogenesis. The European Journal of Neuroscience, 33(6), 1139–51. doi:10.1111/j.1460-9568.2011.07613.x

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God and the Brain

I recently came across a couple articles that inspired the blog post you are now reading. For more information please see the following articles published in Leadership Journal:

“Can Neuroscience Help Us Disciple Anyone” by John Ortberg

“The Sanctified Brain” by Robert Crosby

Neurotheology

Thinking about how our brains perceive and experience God was a question I hadn’t yet asked myself until my Behavioral Neuroscience professor at Wheaton College mentioned it as a field of Neuroscience. “Neurotheology” has been thrown around the last couple years as an emerging sub-field of neuroscience research. Research might include EEG data while a participant is praying a memorized prayer vs. a prayer they make up on the spot or an EEG of a person speaking in tongues vs. singing a favorite hymn.

Those of us who identify with a particular religion whether it be Christian, Islam, Buddhist, etc. identify with feelings experienced during worship music or a really inspiring sermon but where are those “God Circuits” (as Dr. Andrew Newberg from Thomas Jefferson University has called them) located. Furthermore does the fact that we can locate them within a neural network make them any less “spiritual”? What would happen to our salvation (or our ability to become saved) should the areas of our brain responsible for retrieving memories or experiencing God get damaged?

Similarly…

What does the process of sanctification look like neurologically?

We’ve known for some time that our brains are malleable through what we call “neuroplasticity”. Paul’s words in Philippians 4:8 ring especially true given this fact: “Finally, brothers, whatever is true, whatever is honorable, whatever is just, whatever is pure, whatever is lovely, whatever is commendable, if there is any excellence, if there is anything worthy of praise, think about these things.” We are literally re-wiring our brain by what we think about, therefore, focus on things of LIGHT!

So is religion just our brains? Some are quick to jump to what Dr. John Ortberg calls “nothing buttery” (as in “We are nothing but our brains…”). John Ortberg writes, “We are not just our brains. No one has ever seen a thought, or an idea, or a choice. A neuron firing is not the same things a a thought, even though they may coincide.”

We still aren’t sure how electricity makes it’s way into complex thoughts and memories.

Regardless of what the future of neuroscience holds we can take comfort that the God we serve has so equipped us to ask the tough questions and find him not lacking in answers. We are truly “fearfully and wonderfully made”.

SPECT Imaging and Psychiatry

This TED talk by Dr. Daniel Amen makes a good point. Why are psychiatrists the only doctors who don’t use any form of imaging in making their diagnoses? Dr. Amen discuses a newer form of brain scans that can help psychiatrists treat patients better and more effectively. 

Key points:

  • Psychiatrists are the only doctors who “guess” rather than look
  • SPECT can visually represent what is going on in the brain
  • Behavior is an outflow of a condition, not a condition in itself
  • Throwing medication at a problem can cause harm if given in incorrect diagnosis
  • We are not stuck with the brain we have, we can improve it on a “brain-smart” program 

Here is a SPECT image of Alzheimer’s Disease:

Image Credit: 2014 © Cedars-Sinai. All Rights Reserved. A 501(c)(3) non-profit organization

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MSG Effects on Hypothalamus Tissue and Weight Gain in Rats

I came across this image in an article published by Dr. Olney. This is an image of hypothalamus tissue exposed to MSG over time. The white tissue is necrotic.

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Dr. Olney also did research on the effects of MSG on weight gain. Below are two rats from the same litter. The left rat was given MSG and the right rat is the largest rat from the litter given no MSG (serving as experimental control).

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Here is a link to the actual article published in 1991:
Olney (1991)

Excitotoxins: MSG and Dr. Blaylock

I cam across a video by The Health Ranger on YouTube in which he inerviews Dr. Russell Blaylock a Neurosurgoun and the formost authority on excitotoxins in the brain. Here is the video:

Two books are referenced in the video they are:

In Bad Taste: The MSG Syndrome by Dr. George Schwartz

http://www.amazon.com/In-Bad-Taste-Syndrome-Signet/dp/0451165144/ref=sr_1_1?ie=UTF8&qid=1376180199&sr=8-1&keywords=in+bad+taste

and Dr. Blaylock’s first book Excitotoxins: The Taste That Kills

http://www.amazon.com/Excitotoxins-The-Taste-That-Kills/dp/0929173252/ref=sr_1_1?ie=UTF8&qid=1376180278&sr=8-1&keywords=excitotoxins

A couple highlights from the video:

  • MSG first appeared in foods in 1945 and the amount in food has doubled every decade thereafter.
  • Of all of the animals on earth, humans are the most susceptible to MSG toxicity.
  • MSG toxicity (MSG Syndrome) symptoms include: flushing of the face, heart palpitations, GI discomfort and diarrhea, damage to the brain over time that could lead to Alzheimer and Parkinson.
  • MSG can also be labeled as “Yeast Extract” on food labels.
  • Certain foods have naturally occurring MSG. This MSG is bonded, though, to a protein which takes time to break down and allow your body to process the MSG.
  • If you are active, MSG you eat can go to your muscles, if you are sedentary it will go to your brain.
  • Magnesium Pyruvate, Vitamin E and Vitamin C can protect the body from MSG toxicity.

Dr. Russell Blaylock’s website is:

http://russellblaylockmd.com/

A side note: the worlds primary producer of MSG is the Ajinomoto Company

http://www.ajinomoto-usa.com/

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Theanine, Lavander, and GABA

A while back I wrote a post about MSG and its connection to OCD.

After doing more research on natural anxiety supplements I came across L-Theanine. Theanine is able to easily pass through the bodies blood-brain-barrier and increase the levels of GABA (gamma-Aminobutyric acid) promoting relaxation.

An interesting illustration of GABA and its role within a synapse is shown in this illustration form Wikimedia Commons:

A similar increase in GABA was shown in patients who inhaled lavender essential oil. I am working on getting a reliable citation for the connection.

Most of my research is done at work during the rare slow times (I work as a pharmacy technician).

If you have any information about Theanine, Lavendar, GABA, OCD, or Anxiety, please post your information and/or links in the comments section.

 

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MSG (Monosodium Glutamate) and OCD

I noticed about a year and a half ago that I had a real problem with MSG. I don’t eat sushi very often but I remember one particular time I decided to load up on soy sauce. Later that day I had a pounding headache, the worst upset stomach, and it was difficult to breath. 

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I did some research on MSG and found that people who have OCD also have a small increase in the neurotransmitter “Glutamate”. (Read this article for a study done with OCD patients: http://img2.tapuz.co.il/forums/1_143264754.pdf )

I’ll have to find the citation but I remember another study talking about the role of Glutamate and the frontal lobe (see my first post).

Anyone else have similar problems with MSG? (Or MSG and OCD?)

Here is a picture of the structure of the neurotransmitter Glutamate:

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The Left Anterior Orbitofrontal Cortex

My first year of undergraduate education I was shocked when my professor told me that the disorders listed in the Diagnostic and Statistical Manual for Mental Disorders were disorders we knew how to treat, but didn’t know the causes.
I want to focus my work not just on treatments but causes.
On that note I have been reading about the Left Anterior Orbitofrontal Cortex. An area of the brain believed to play a role in causing Obsessive Compulsive Disorder.
I don’t have a lot of information to share as of right now but I plan on continuing my research in this area.
If you have any information about this specific region (or even areas of the frontal lobe in general) please feel free to share!

For more information on this region regarding its role in “secondary reinforcers” see this wordpress blog I found:
Secondary Reinforcers

I don’t want the knowledge I have received from even the small amount of education I have currently received to go to waste. It’s time to start looking for causes so we can start working on prevention.

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