Short Article on Alzheimer’s Disease: #1 Amyloid beta Formation

Alzheimer’s disease is a devastating condition with currently no cure or treatment to halt its progression. It is an unremitting neurodegenerative disorder, causing slow and progressive cognitive impairment and is the major known cause of dementia. Although some treatments exist to temporarily relieve some of the symptoms such as memory loss and co-morbid illnesses such as cerebrovascular diseases, patients mostly rely heavily on the support received from their social network. This condition was first described by Alois Alzheimer in 1907 and later histological analyses of brain tissues of patients with these symptoms showed proteinaceous aggregates, also called senile plaques, containing insoluble forms of amyloid beta. [1]

Formation of Amyloid beta from APP

Amyloid beta is derived from amyloid precursor protein or APP, which is found in the membrane of neurons and plays a important role in neuron growth and repair after an injury. It is usually processed and cleaved sequentially by two enzymes, alpha and gamma secretases. The resulting fragments from this cleavage are soluble, non-toxic to neurons and in healthy brains are broken down and eliminated. However, if the cleavage by alpha secretase is inhibited, APP is cleaved by beta-secretase (BACE) and gamma secretase consisting of the proteins presenilin 1/presenilin 2, nicastrin, PEN-2 and APH-1.[2] This results in the formation of the fragments amyloid beta 40-42 with the most aggregation-prone fragment amyloid beta 42, to form amyloid plaques in the extracellular space. These plaques weaken the communication and plasticity at synapses and can also deposit around blood vessels in the brain causing amyloid angiopathy and hence increase the likelihood of haemorrhages.[1]

The Multiple Forms of Amyloid beta [3-6]
Amyloid beta peptides are intrinsically disordered proteins (IDPs), meaning they are extremely flexible with no fixed or three-dimensional structures. They undergo rapid conformation changes and fast aggregation processes and as a result exist as multiple forms with distinct polymorphic structures. It is believed that amyloid beta oligomers are the most neurotoxic species, however their study is challenging as different preparation methods might lead to the generation of different oligomeric intermediates which are hard to compare between studies. Several conformation-dependant antibodies exist and are able to recognise generic epitopes that are associated with specific aggregation states on amyloid-forming proteins and this independently of the amino acid sequence. For instance, A11 antibodies can recognise out-of-register anti-parallel beta sheet structures, whereas OC antibodies detect in-register parallel beta sheets.[5]

Newmarket Scientific, a distributor of Life Science reagents in the UK and Ireland, represents several suppliers that provide high quality reagents for Alzheimer's disease research. Below are some product highlights for amyloid beta research.

Further reading
- Amyloid beta plaque staining
- Short Articles on Alzheimer’s Disease:
#2 Amyloid beta accumulation, imbalance of the production and clearance of Abeta
#3 Microglia
#4 Tau Phosphorylation
#5 Tau Aggregation and Propagation
 
References
[1] Alzheimer Disease, Kuma A. et al, Treasure Island (FL): StatPearls Publishing; 2018 Jan
[2] Alzheimer’s Disease, Masters C. et al. Nature reviews Disease Primers 1, article number 15056, 2015
[3] Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology, Coskuner-Weber O. et al., Int J Mol Sci. 2018 Feb; 19(2): 336.
[4] Structural Classification of Toxic Amyloid Oligomers, Glabe C.G, J Biol Chem. 2008 Oct 31; 283(44): 29639–29643.
[5] Amyloid-β Receptors: The Good, the Bad, and the Prion Protein, Jorosz-Griffiths H.H. et al, J Biol Chem. 2016 Feb 12; 291(7): 3174–3183.
[6] Crucial role of protein oligomerization in the pathogenesis of Alzheimer’s and Parkinson’s Diseases, Choi M.L et al, FEBS J. 2018 Jun 20.
[7] A Generic Method for Design of Oligomer-Specific Antibodies, Brännström et al., PLoS One. 2014 Mar 11;9(3):e90857.
[8] Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody, Youmans K. et al., Mol Neurodegener. 2012; 7: 8.

Written by Magalie Dale
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