Drugs for alzheimer's disease: the structure of enlightenment

April 15, 2017

From caixin

Source: "the intellectuals"

Writing | Liu Jun chardonnay (Shanghai), assistant professor of university of science and technology

Editor's note:

In November 2016, the American pharmaceutical giant eli lilly announced its costly research and development of failure solanezumab alzheimer's drug research and development, the market reacted strongly, lilly's shares fell 14%. On drugs for alzheimer's disease, is not only polite to company forays, tasted defeat many pharmaceutical companies, but they fell more courage and commitment. Solanezumab for b - amyloid peptide (A - b) soluble monomer molecules in the middle area of antibody, the protein has toxicity to the nerve, aggregations can cause the death of neurons. Recently, A set of scientific research team composed of Chinese and foreign scholars have found that A - b amyloid fiber polymer in the body structure is complicated, for the different types of alzheimer's drug research and development and in view of the different types of A - b inhibitors of the polymer structure design provides A new way of thinking. "Intellectuals" invited to this paper, for the study.

Alzheimer's disease and alzheimer's disease. At present, China has become the most populous country in patients with alzheimer's disease, however, only about 21% of the patients really went to go to a doctor. Patients with alzheimer's disease is no cure, but needs to long-term health care, so we need more effective diagnosis and treatment.

Patients with alzheimer's disease will first show cognitive ability is gradually lost, eventually die. From the point of histopathologic, an important characteristics of the disease is to get the disease of the patient's brain contains A lot of b - amyloid peptide (A - b), and aggregated into fibrous deposition.

Hypothesis of alzheimer's disease amyloid protein aggregation will cause the death of neurons in the brain, the protein fiber with neurotoxicity. More studies have found that A - b can form and the multiple structure of the fiber in vitro, then the diversity of structure and alzheimer's disease is what relation? In past research, the fibrous structure of A - b A - b fibers are spontaneous aggregation in vitro and its structure does not necessarily represent the patient brain amyloid protein polymer structure, so A - b fiber in the patient's brain structure and how?

To answer these questions, the national institutes of health, Robert Tycko and colleagues for a set of extracted from donor patient brain amyloid protein polymers. They found can again from a patient's brain tissue samples of amyloid protein polymer as a seed for in vitro amplification, more can be used in the preparation of solid nuclear magnetic resonance (ssNMR) the amyloid fiber structure analysis.

Recently, the journal Nature reported from Robert Tycko team, strong by wei as the first author (now at the state university of New York at Binghamton) of an article, 18 are studied by this method, A total of 37 patients with brain tissue samples of A - b fiber. Including these patients suffering from alzheimer's typical (t - AD), and the discovery of two rare subtypes: type rapid progress in alzheimer's disease (r - AD), and visual processing obstacle of cortical atrophy type after alzheimer's disease (PCA - AD). Article attempts through nuclear magnetic spectra judgment of these different types of patients with alzheimer's disease brain amyloid protein fiber with different conformation, looking for the amyloid protein fibers of different conformation and the relationship between different types of alzheimer's disease. Due to the body of A - b peptides have different length, the most A - b containing 40 amino acid residues containing 40 and 42 amino acid residues of A - b 42, this article separately for the two peptide amyloid protein fiber were studied.

The authors found that for A - b 40, the t - AD and PCA - AD samples, A kind of special fiber structure are dominant, and judging from the chemical shift, the structure and the group has reported another the fibrous structure of A - b 40 patients. R - AD samples are presented and various different A - b 40 fiber structure. For these different types of dementia, A - b 42 of the amyloid fiber structure has more diversity, the lack of A unified structure.

Although this article did not resolve the new structure of the amyloid fiber, but the article results tell us that alzheimer's disease amyloid protein fiber in the body structure is varied, the different clinical subtypes of alzheimer's disease in the brain tissue protein fiber structure can be different, some types of alzheimer's disease amyloid fiber structure is consistent. These structures are quite different from the laboratory spontaneous aggregation form A - b fiber structure.

A - b protein aggregation can form the large molecular weight protein fiber and can also form oligomers, structure of small molecular weight. Although A variety of different polymer structure, size is differ, but no matter what kind of A - b the most toxic, A key drug design should be to reduce the generation of A - b peptide or inhibit the aggregation. At the end of 2016, the American pharmaceutical giant Eli lilly (Eli Lily & Co.) renounced its solanezumab mild alzheimer's drug treatment of further research. Solanezumab is on A - b antibody protein soluble monomer molecules between area. Stop for this work, different people have different understanding. Many people think that this is for alzheimer's disease amyloid hypothesis of negation. In addition to the amyloid hypothesis, there are other hypothesis of alzheimer's disease pathogenesis, such as nerve inflammation, excessive tau protein phosphorylation or glucose metabolism. So far, but it must be noted that are aimed at inhibiting A - b protein drug development, there are eight at the FDA phase III (phase 3) experimental drug, one of the drugs hope of success.

Above work shows that the body A - b amyloid fiber polymer structure is complicated, it also brought difficulty to the design of drugs. Maybe we should according to different types of alzheimer's disease and different types of A - b polymer structure design different inhibitors or drugs. For alzheimer's disease developed by the failure of certain drugs may be because we neglected the diversity of its structure.