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Protein structure is directly associated with protein function. Proteopathies are a broad class of diseases where abnormalities in protein structure result in abnormal configuration, protein misfolding or toxicity. These diseases are a major burden of human and agricultural animal health and result in multiple debilitating or fatal diseased states. A list of proteopathic diseases is located below. For this assignment, you will choose one of these diseases and assess several criteria in the form of a mini-review article suitable for publication in a scientific journal.

Human Prion Diseases:

  • Creutzfeldt-Jakob Disease (CJD)
  • Cystic Fibrosis
  • Alzheimer's disease
  • Sickle cell disease

Animal Prion Diseases

  • Bovine Spongiform Encephalopathy (BSE)
  • Chronic Wasting Disease (CWD)
  • Feline spongiform encephalopathy
  • Scrapie

The remainder of the word count (900 words) should make up the body of your review. This should include the following information:

a. A description of the molecular events that cause your protein of interest to adopt an abnormal state.
b. Explain how abnormal protein structure leads to disease and discuss current treatments.
c. Finish your review with a conclusion that offers the reader a take-home message of your review.

Protein Misfolding and Proteopathies

The prevalence of Alzheimer’s disease is most common in the elderly people above the age of 65 years old. This neurodegenerative disease has been a major burden on the healthcare system universally and its occurrence is also expected to rise in the coming years. The disease impairs cognitive functions and loss in memory of the patients as it progresses clinically (Dubois, et al., 2016). The disorder in the adults is due to abnormal misfolding of amyeloid beta (Aβ) proteins in the brain. The prominent attributes reported from the brain tissues of Alzheimer’s patients are intracerebral deposits of amyloid plaques, neurofibrillary tangles, and excessive granulovacuoles (Yuyama and Igarashi, 2017). The communication between the neuron cells or synapse is affected due to such amyloid-beta accumulation leading to plaque formation outside the neurons. These abnormal structures block the signaling among neurons and vital cell functioning is affected and finally result into death or dysfunction of neurons.  

Reports have suggested the noteworthy feature of particular proteins which can misfold abnormally and accumulate to turn into seeds. Protein misfolding has been linked with many disorders of brain. The proteins are free from regulation and self-assemble themselves into aggregates, which is a general tendency of major proteins (Lyubchenko, 2015).These altered protein structures act as infective collections which range from oligomers to amyloids of large masses. Thus, these seeds or modified protein structures function as factors to propagate themselves to trigger the advancement of disease and spread from neuron to neuron (Selkoe and Hardy, 2016). The oligomers of Aβ of 42 residues are assumed to be soluble and most toxic form. They attach to synapses of neuron and function as infectious ligands. Cytotoxicity is attributed to these oligomers of Aβ 42 as it declines the neuronal synapses.

Economou and co-workers have reported direct imaging through high resolution atomic force microscopy that Aβ 42 protein dimers, hexamers or dodecamers assigned to become dominant oligomers which are observed as aggregations at earlier stages of Alzheimer’s (Economou, et al., 2016). The preprotofibril were single linked with dodecamer of Aβ 42 layer and could extend to length of nearby hundred nanometers. In case of Aβ 40 residue, it was reported that hexamer or dodecamer are not formed only small oligomers are formed which result into branched chain like network and not discrete structures (Economou, et al., 2016). Therefore, these proteopathies seen in Alzheimer and other cerebral diseases appear to develop from misfolding and corruption of protein which eventually result into dysfunction of neural synapse.

The molecular mechanism has unfolded the mystery behind the pathophysiology of the course of Alzheimer’s. The available literature suggests that neuropathological events in Alzheimer’s have been exhibited in a cascade of advanced order which is detected by using dynamic biomarkers in vivo. Amyloid-beta proteins have numerous isoforms which range from 37 to 49 amino acids by proteolysis of amyloid precursor protein (APP) (Um and Strittmatter, 2013). This (APP) is an inherent protein which is found concentrated in the neuron synapses region and also expressed in various tissues. Its function is to maintain neuron plasticity, export of iron and regulation of synapse establishment. The formation of Aβ- 42 results due to action of β and γ secretases during proteolysis of precursor APP (Sakae, et al., 2016). 

Molecular Mechanism of Alzheimer’s Disease


Figure (1) describes formation of amyloid-beta by proteolysis. The two proteases β and γ secretases, the activity of β secretase is facilitated by type I membrane protein called β-site-APP-cleaving enzyme (BACE 1). For the γ-secretase the activity is facilitated by an intramembrane complex containing presenilin this holds the catalytic domain (Yuyama and Igarashi, 2017).

Among these isoforms, amyloid-beta 42 has exhibited the maximum tendency to accumulate into extracellular spaces around neurons and therefore, it is found to be related to brain disorders and Alzheimer’s (Lesne, et al., 2013; Dohler, et al., 2014). Proteins form elongated fibres which are unbranched with backbone comprising of stranded beta sheets and get into amyloid state. Proteins move into amyloid state on exposing their backbone of amide group (NH) and carbonyl group (C=O), allowing these groups to form hydrogen bonds with different chains of proteins (Eisenberg and Jucker, 2012).

Presently, few researchers suggest that amyloid-beta oligomers tie up to the plasma membrane-bound cellular prion protein (PrPC) at N-terminus, and eventually follow the degeneration of synapses. However, the binding of amyloid β42- PrPC complex renders an essential understanding of the pathophysiology regarding degeneration of neural cells in Alzheimer’s. (Westaway and Jhamandas, 2012; Um and Strittmatter, 2013). Studies have also reported the flexibility of N-terminus of PrPC and revealed the binding site of Aβ to 23-27 and 95-110 residue sites of PrPC (Dohler, et al., 2014). PrPC is a glycoprotein of neurons and its function is still unknown.

The function of Tau protein is to make steady the microtubules on phosphorylation, hence it is known as microtubule associated protein. Tau protein gets phosphorylated in an aberrant manner and then ultimately accumulates in the fibrils such as thread formation in neuropil and in soma as tangles (Crespo-Biel, et al., 2012). The threads produce neurofibrillary tangles (NFT). This as a result impairs neural communication through synapses and eventually turns into dysfunction of cognitive functions. Therefore, reports justified that Tau proteins are accountable for failure of synaptic plasticity and toxicity along with cognitive functions (Crespo-Biel, et al., 2012). The pathophysiology is marked by the onset of amyloid deposition and traced by accumulation of tau which is hyper-phosphorylated. This consequently affects the structure, function and cognitive behaviour in a gradual declining manner (Jack, et al., 2013). Therefore, the synergistic effect of amyloid-beta and tau proteins have been mentioned as determining factors in Alzheimer’s declination both structurally and metabolically (Pascoal, et al., 2017).

These amyloid plaques are formed exterior to the neuron cells and through seeding infect neighbouring neuron communication as well as intracellular transport. Due to aggregation of proteins which triggers immunity and cause cellular stress neural cells deteriorate and loss of synapses ultimately leads to cognitive and behavioural disability (Lyubchenko, 2015). Therefore, elderly patients face difficulties to remember information and perform daily activities. The loss in memory is progressive and the disorder in brain is irreversible. The accumulation of amyloid-beta plaques takes place over a time period of 15 years before even the beginning of symptoms (Yuyama and Igarashi, 2017).

Amyloid-Beta Accumulation in Alzheimer’s and its Role in Proteopathies

Since decades, numerous efforts in therapeutical drug research for Alzheimer’s are still exploring potential targets because till date there is no remedy (Graham, et al., 2017). Presently in the market four drugs are available which are in generic form and are prescribed based on cognitive tests. Three of the drugs have anticholinesterase property and galantamine and act on central nervous system. Especially for Alzheimer’s the drug memantine is approved in United States which targets glutaminergic pathways and N-methyl-D-aspartate (NMDA) receptor. Based on the recent reports, an addition to pathophysiological mechanism for Alzheimer disease is excess glutamate at neuronal synapses related with toxicity which is probably responsible for less uptake of glutamate from microglia. The postsynaptic glutamate inhibitor is still under clinical trial II (Graham, et al., 2017). None of drugs has been proved safe for long term use or efficient in regulating the pathology of the disease. These drugs have been used to slow down the decline in cognitive behavioural functions and generally used in palliative care to provide symptomatic relief by improving quality of life.


Alzheimer’s is an age-linked disease, and worldwide tremendous groundwork and numerous schemes have been applied to provide an insight to reveal pathophysiology of the disease. Yet, less success with Alzheimer’ have been achieved, because till now no particular drug has been discovered which will modify the mode of action of this chronic disease. Alzheimer’s is a challenging disease; it is elusive to study its mechanism, identifying biomarkers, and decipher therapy as well as designing of clinical trials, still hope has come by knowing hallmarks of Alzheimer’s. The histopathology of the disease is explicitly exposed by the pathways of amyloid-beta and tau proteins which have helped to understand the seeding of plaque formation. This motivates the researchers to develop substantial drug research and programs to conquer this chronic disease.


Crespo-Biel, N., Theunis, C., and Van Leuven, F. (2012). ‘Protein Tau: prime cause of synaptic and neuronal degeneration in Alzheimer’s disease’, International Journal of Alzheimer’s Disease. Article ID 251426. Online available from doi:10.1155/2012/251426 (Accessed 16/3/12)

Dohler, F., Sepulveda-Falla, D., Krasemann, S., Altmeppen, H., Schlüter, H., Hildebrand, D., Zerr, I., Matschke, J., and Glatzel, M. (2014). ‘High molecular mass assemblies of amyloid oligomers bind prion protein in patients with Alzheimer’s disease’, Brain, 137, pp. 873-886.

Dubois, B., Padovani, A., Scheltens, P., Rossi, A., and Dell’Agnello, G. (2016). ‘Timely Diagnosis for Alzheimer’s Disease: A Literature Review on Benefits and Challenges’, Journal of Alzheimer’s Disease, 49(3), pp. 617-631.

Economou, N. J., Giammona, M. J., Do, T. D., Zheng, X., Teplow, D. B., Buratto, S. K., and Bowers, M. T. (2016). ‘Amyloid β-protein assembly and Alzheimer’s disease: Dodecamers of Aβ42, but not of Aβ40, seed fibril formation’, Journal of the American Chemical Society, 138(6), pp. 1772-1775.

Eisenberg, D., and Jucker, M. (2012). ‘The amyloid state of proteins in human diseases’, Cell, 148(6), pp. 1188-1203.

Graham, W. V., Bonito-Oliva, A., and Sakmar, T.P. (2017). ‘Update on Alzheimer’s disease therapy and prevention strategies’, The Annual Review of Medicine, 68, pp. 413-430.

Jack, C. R., Knopman, D. S., Jagust, W. J., Petersen, R. C., Weiner, M. W., Aisen, P. S., … and Trojanowski, J. Q. (2013). ‘Update on hypothetical model of Alzheimer’s disease biomarkers’, Lancet Neurology, 2(2), pp. 207-216.

Lesne, S. E., Sherman, M. A., Grant, M., Kuskowski, M., Schneider, J. A., Bennett, D. A., and Ashe, K. H. (2013). ‘Brain amyloid-β oligomers in ageing and Alzheimer’s disease’, Brain, 136(5), pp. 1383-1398.

Lyubchenko, Y. L. (2015). ‘Amyloid misfolding, aggregation, and the early onset of protein deposition diseases: insights from AFM experiments and computational analyses’, AIMS Molecular Science, 2(3), pp. 190-210.

Pascoal, T. A., Mathotaarachchi, S., Mohades, S., Benedet, A. L., Chung, C.-O., Shin, M., … and Rosa-Neto, P. (2017). ‘Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease’, Molecular Psychiatry, 22(2), pp. 306-311.

Sakae, N., Liu, C.-C., Shinohara, M., Frisch-Daiello, J., Ma, L., Yamazaki, Y., … and Kanekiyo, T. (2016). ‘ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer’s Neuronal Pathology’, The Journal of Neuroscience, 36(13), pp. 3848-3859.

Selkoe, D. J., and Hardy, J. (2016). ‘The amyloid hypothesis of Alzheimer’s disease at 25 years’, EMBO Molecular Medicine, 8(6), pp. 595-608.

Um, J. W., and Strittmatter, S. M. (2013). ‘Amyloid-beta induced signalling by cellular prion protein and Fyn kinase in Alzheimer disease’, Prion, 7, pp. 37-41.

Westaway, D., and Jhamandas, J.H. (2012). ‘The P’s and Q’s of cellular PrP-Abeta interactions’, Prion, 6, pp. 359-63.

Yuyama, K., & Igarashi, Y. (2017). ‘Exosomes as Carriers of Alzheimer’s Amyloid-ß’, Frontiers in Neuroscience, 11, pp. 229.

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