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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