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Only one key aspect distinguishes the proteins that trigger Alzheimer's from those involved in memory consolidation.

A study led by the Cajal Institute finds a crucial difference between "bad" and "good" amyloid protein aggregates.

The research could provide new targets for prevention, early diagnosis and treatment of neurodegenerative diseases.

A group form the Cajal Institute has found a key difference between amyloid proteins that trigger neurodegenerative diseases such as Alzheimer's, which are neurotoxic, and those involved in memory consolidation, which are "good" amyloids. The study, published in the journal PLoS Biology, and selected with a special comment in the highlighted articles section, could provide new targets for prevention, early diagnosis and treatment of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and Mad Cow Disease.

In 2003, the laboratory of the Nobel laureate Eric Kandel found that CPEB/Orb2, a key protein in memory consolidation, behaved like a prion, similar to the mechanism of the infectious agent of disease in Mad Cow Disease, but as a “good” prion.

In this new study developed in collaboration with the discoverer of this protein, Kausik Si, now at the Stowers Institute (United States), the researchers found that CPEB/Orb2 shares most of the characteristics of the aggregation route of the neurotoxic proteins, a pathway typically associated with neurodegenerative diseases.

The study highlighted that the CPEB/Orb2 family of proteins are extraordinary similar to neurotoxic proteins so they can even be sequestered by the last ones, forming hybrid amyloids, which could explain the memory impairment seen in many of these diseases before neuronal death. However, it was also found a crucial difference: the toxicity of CPEB/Orb2 is transient in nature.

The toxic species CPEB/Orb2 disappears very quickly, which makes this amyloid not toxic. Nevertheless, the aggregation route is so similar in both proteins that both could be blocked by the same inhibitor agent, the synthetic peptide QBP1.

Potential drug.

This work, developed in the laboratory of Dr Mariano Carrión Vázquez, and funded by MINECO, provides some light to understand the molecular mechanism that trigger the toxicity of neurotoxic proteins. This could allow decoding the primary cause of these diseases and therefore represents a breakthrough in both, prevention and diagnosis of these diseases enabling the design of more specific and effective new drugs.

Also, these scientists have taken advantage of the great similarity between "good" and "bad" amyloids to make another important discovery. QBP1, a potential drug originally developed to treat Huntington's disease, is able to block memory consolidation. Thus, they showed that QBP1 inhibits the formation of CPEB/Orb2 amyloid aggregates necessary to carry out their function, and thereby blocking memory consolidation. This specific effect makes QBP1 a good candidate for the prevention and treatment of Post-Traumatic Stress Disorder and related diseases.

References.

Rubén Hervás, Liying Li, Amitabha Majumdar, María del Carmen Fernández-Ramírez, Jay R. Unruh, Brian D. Slaughter, Albert Galera-Prat, Elena Santana,Mari Suzuki, Yoshitaka Nagai, Marta Bruix, Sergio Casas-Tintó, Margarita Menéndez, Douglas V. Laurents, Kausik Si, y Mariano Carrión-Vázquez. Molecular basis of Orb2 amyloidogenesis and blockade of memory consolidation. PLOS Biology. DOI:10.1371/journal.pbio.1002361.
http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002361

Comment:

Roberts RG (2016) Good Amyloid, Bad Amyloid - What’s the Difference? PLoS Biol 14(1): e1002362. doi:10.1371/journal.pbio.1002362.
http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002362


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