Amyloid structure linked to different types of Alzheimer’s disease

Cutting edge imaging shows that the amyloid fibers in plaques, a hallmark of Alzheimer’s disease, have different molecular structures. NIA-supported research published in Science shows new, high-resolution images of the molecular pieces, called filaments, which make up amyloid plaques in different types of Alzheimer’s and in other degenerative brain conditions.

Amyloid plaques form in the brains of people who have Alzheimer’s and can lead to problems with brain function. All amyloid plaques begin as strings of amino acids called amyloid-β (Aβ) peptides. The structure of Aβ peptides varies depending on how many amino acids they contain. An Aβ peptide with 42 amino acids, called Aβ42, is the most common in plaques. Older adults who do not have dementia can have low levels of Aβ42 peptides. However, in people with Alzheimer’s and other degenerative brain conditions, these peptides are much more common, and they form larger structures called protofilaments. These protofilaments come together to form filaments that aggregate to make amyloid plaques.

To better understand the structure of amyloid plaques, an international team of researchers collected post-autopsy brain tissue from 10 individuals. At the time of death, five of the individuals had Alzheimer’s; two had inherited, or familial, Alzheimer’s, which often develops earlier in life; and three had sporadic Alzheimer’s, which is not inherited and typically occurs later in life. The other five people had other degenerative brain conditions unrelated to Alzheimer’s. Researchers extracted Aβ42 filaments from the tissue samples and used cryo-electron microscopy (cryo-EM) to examine the filaments’ structure. Cryo-EM uses very low temperatures to capture 3D images of microscopic structures.

The researchers found two distinct forms of Aβ42 filaments, which they called type I and type II. Their study showed that type I Aβ42 filaments in the brain are made of two identical S-shaped protofilaments. Each protofilament has an arm-like structure that extends to contact the other. Type II Aβ42 filaments are also made of identical S-shaped protofilaments, but they do not have the same arm-like extensions. Importantly, the two structures differed from those in previous experiments using brain cells grown in a laboratory.

Type I Aβ42 filaments were most abundant in the brains of people with sporadic Alzheimer’s, while type II Aβ42 filaments were most abundant in inherited Alzheimer’s. Type II Aβ42 filaments were also more common in the samples from the people who had other degenerative conditions.

Interestingly, a genetically altered mouse model of Alzheimer’s that scientists often use to study the disease’s molecular and behavioral characteristics also had filaments identical to the type II Aβ42 filaments found in humans. That mouse model finding underscored the benefits of using this mouse model to help scientists learn more about inherited Alzheimer’s in humans.

The findings from the human study may enable researchers to better understand the molecular features of amyloid plaques in the brain. This improved understanding may also allow for the development of new animal models, imaging techniques, and targeted treatments for different types of Alzheimer’s disease.

This research was supported in part by NIA grants P30AG010133 and RF1AG071177.

These activities relate to NIA’s AD+ADRD Research Implementation Milestone 2.H, “Continue to support cross-disciplinary research to discover and understand disease mechanisms that are common between AD and other neurodegenerative disorders including rare disorders and leverage these for therapy development. These efforts should include discovering new pathways leading to synaptic and neural damage understanding the structural variations of pathogenic peptides collected from well-phenotyped, diverse cohorts to inform the design of structure-specific imaging agents and inhibitors with therapeutic potential.”

Reference: Yang Y, et al. Cryo-EM structures of amyloid-β 42 filaments from human brains. Science. 2022. Epub Jan. 13. doi: 10.1126/science.abm7285

by NIH National Institute on Aging (NIA).