FANDOM


ChkNFH-neuron3

Rat neuron stained with chicken anti neurofilament (NF-H) http://www.encorbio.com/Album/pages/ChkNFH-neuron3.htm

Alzheimer's Disease (AD) was first reported by Dr. Alois Alzheimer in 1906 (1). Following the death of a patient who suffered from memory loss, impaired language skills and unpredictable behavior, Dr. Alzheimer performed a post mortem study of her brain (1). He found structures that would eventually be called β-amyloid plaques and neurofibrillary tangles (NFTs) (1)

Biology of the DiseaseEdit

The symptoms of AD are directly related to neuronal degeneration. There are many researchers invested in teasing out the processes that lead to the development of AD. It has been shown that NFTs disrupt fast axonal transport (FAT) within the neuron (2). FAT is the motor protein mediated transport of cargo on microtubules (MTs) (3). Cargo is trafficked both towards the cell body (retrograde) and away from the cell body (anterograde) (4). The motor proteins kinesin-1 and -2 mediate anterograde transport within the axon while cytoplasmic dynein mediates retrograde transport (4). This axon to synapse transport of cargo may seem trivial but, the fact that a neuron can be up to a meter long should put the importance of FAT into perspective. It is also important to remember that the environment within the neuron is extremely crowded so the passive movement of organelles (ex. mitochondria) and other cargo would not be a viable option for the cell. Motor proteins and MTs are not the only components of this transport system. Enzymes and other MT associated proteins (MAPs) are needed to help direct MT growth, regulate loading and unloading of cargo and stabilize MTs. One neuronal MAP, tau, has been shown to help stabilize MTs (5), interact with the actin cytoskeleton (6), participate in signaling pathways (2) and inhibit kinesin-1 run length in vitro (3). Though tau's exact role in AD has yet to be fully elucidated, hyperphosphorylated tau is a component of NFTs which are known to disrupt FAT (2).

β-amyloid plaques are extracellular deposits of β-amyloid peptide. β-amyloid peptide is the product of cleavage of the amyloid precursor protein (APP) (7). Normal APP function is not completely understood (8) . It has been shown that it performs many functions including enzyme activation (9)  and protection from oxidative stress (10). It is hypothesized that cleavage of APP and its aggregation into β-amyloid plaques is responsible for the pathology seen in the AD brain and for the symptoms of AD (7)

Plaque and tangle

AD brain tissue sample showing β-amyloid plaque and NFT. https://gbiomed.kuleuven.be/english/research/50000622/50525540/alzheimers-disease

John's 23andMe ResultEdit

According to the 23andMe analysis, John has typical odds of developing AD. The marker/SNP (single nucleotide polymorphism) that 23andMe analysed was rs63750847. The typical genotype for this SNP is CC. CT and TT genotypes have reduced odds of developing AD. Recent research found that this C -> T mutation occurs next to an aspartyl protease cleavage site (11). This mutation may prevent/reduce cleavage of APP which in turn reduces the formation of β-amyloid plaques (11). There is no need to be concerned about this genotype or the possible phenotype (AD) that may result since his odds are not elevated. It should also be noted that the study which found the C -> T mutation was done in an Icelandic population of 1,795 people (11) and that the relevance of this study to other populations has yet to be established. It might be that this mutation only occurs in this population and that the findings of this study do not extend beyond the Icelandic population in which it was conducted.

ReferencesEdit

1.  Wikipedia (2013) Alois Alzheimer, http://en.wikipedia.org/wiki/Alois_Alzheimer

2.  Kanaan NM, et al. (2012) Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport. Neurobiology of aging 33(4):826 e815-830.

3.  Dixit R, Ross JL, Goldman YE, & Holzbaur EL (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 319(5866):1086-1089.

4.  Ballatore C, Lee VM, & Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nature reviews. Neuroscience 8(9):663-672.

5.  Cleveland DW, Hwo S-Y, & Kirschner MW (1977) Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. Journal of molecular biology 116(2):227-247.

6.  He HJ, et al. (2009) The proline-rich domain of tau plays a role in interactions with actin. BMC cell biology 10:81.

7.  Wikipedia (2013) Beta amyloid, http://en.wikipedia.org/wiki/Beta_amyloid

8.  Hiltunen M, van Groen T, & Jolkkonen J (2009) Functional Roles of Amyloid-β Protein Precursor and Amyloid-β Peptides: Evidence from Experimental Studies. Journal of Alzheimer's Disease 18(2):401-412.

9.  Bogoyevitch MA, Boehm I, Oakley A, Ketterman AJ, & Barr RK (2004) Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1697(1–2):89-101.

10. Zou K, Gong JS, Yanagisawa K, & Michikawa M (2002) A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. The Journal of neuroscience : the official journal of the Society for Neuroscience 22(12):4833-4841.

11. Jonsson T, et al. (2012) A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488(7409):96-99.