STUDY. The Analytical Neurochemistry research group in Mölndal recently published a study detailing chemical changes in the deposits of the protein beta-amyloid in the brain. This protein is characteristic of Alzheimer’s disease.
Alzheimer’s disease is very common in older people — one in eight aged over 65 suffer from it. Despite intensive research all over the world, the exact mechanism behind the disease remains unknown. The most characteristic feature of Alzheimer’s disease is the plaques, composed of misfolded beta-amyloid (Aβ) peptides, that accumulate in the brain.
“Understanding how plaques of beta-amyloid cause Alzheimer’s to develop is a major challenge, since the disease looks so different in different people, and the plaque morphology and therefore its appearance also vary,” says Jörg Hanrieder, Associate Professor at the Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology.
Advanced chemical imaging
Plaques examined under a microscope may have a diffuse appearance or be more aggregate and compact. Diffuse plaques occur in people who have not developed dementia, as well as those who have. This suggests that the more compact plaques found in those with Alzheimer’s are the critical ones in the disease’s development.
“In our study, we used a new method of multimodal chemical imaging of individual plaques in single tissue samples. This technique combines hyperspectral microscopy and mass spectrometry imaging,” Hanrieder says.
“We use fluorescence microscopy,” he continues, “with structural-specific chemical probes that recognize the structural complexity of beta-amyloid plaques, along with chemical imaging based on MALDI [Matrix-Assisted Laser Desorption/Ionization] mass spectrometry, which allows imaging of the beta-amyloid’s individual peptide variants that make up the various types of amyloid plaques.”
Brain tissue studied
Using this method, the research group studied brain tissue from deceased patients with Alzheimer’s disease, and also examined plaques found in brain tissue from deceased people without dementia.
“We were able to see that both diffuse and compact plaques in brain tissue from people with Alzheimer’s disease have a significantly higher proportion of a type of beta-amyloid peptide called Aβ3pE-42, which is modified with pyroglutamate. We also show that both in human samples and in a genetic mouse model, maturation of plaques from the diffuse into the more compact state is associated with large-scale accumulation of a peptide called Aβ1-40, which forms a characteristic core structure in compact plaques,” Hanrieder says.
The results indicate that formation of the plaques that are toxic for the brain is preceded by a pyroglutamation process in the Aβ42 peptides, making them more fluid-resistant (hydrophobic). This, in turn, can lead to accumulation of the more fluid-soluble Aβ40 peptides as well.
Title: Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1-40 deposition underlies plaque polymorphism in progressing Alzheimer’s disease pathology.
Authors: Michno W, Nyström S, Wehrli P, Lashley T, Brinkmalm G, Guerard L, Syvänen S, Sehlin D, Kaya I, Brinet D, Nilsson K Peter R, Hammarström P, Blennow K, Zetterberg H, and Hanrieder J.*
Journal: Journal of Biological Chemistry, February 27, 2019. doi: 10.1074/jbc.RA118.006604.
TEXT: ELIN LINDSTRÖM CLAESSEN
Compact plaques have mature amyloid structures that are identifiable by their specific spectral signatures (II). The researchers’ results show that Aβ1-40 but not Aβ1-42 aggregates at the compact core structures of these plaques (III).).
Titel: Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1-40 deposition underlies plaque polymorphism in progressing Alzheimer’s disease pathology.
Författare: Michno W, Nyström S, Wehrli P, Lashley T, Brinkmalm G, Guerard L, Syvänen S, Sehlin D, Kaya I, Brinet D, Nilsson KPR, Hammarström P, Blennow K, Zetterberg H, and Hanrieder J.*
Tidskrift: Journal of Biological Chemistry 2019 Feb 27. doi: 10.1074/jbc.RA118.006604.
TEXT: ELIN LINDSTRÖM CLAESSEN
