Researchers have discovered a previously unknown folding of beta-amyloid filaments associated with an extremely rare form of Alzheimer's disease. This structure potentially explains why the protein concentrates around blood vessels and is linked to cerebral hemorrhages.
The study analyzed brain tissues from two patients who had the Flemish mutation in the precursor gene for beta-amyloid (APP). This mutation was identified in two families and two other individuals, typically leading to death by the late fifties.
The researchers examined the brain samples of these two patients after their deaths. Both belonged to known families with this form of dementia.
Cryo-electron microscopy (cryo-EM) was used to visualize the filaments—a method that allows observation of structures at near atomic resolution. The result showed a specific Z-shaped configuration that had not been previously identified.
The geometry of this structure may play an important role in understanding protein behavior, as the filaments tend to aggregate around blood vessels. The folding makes the amino acid F20 accessible. According to the researchers, this feature may contribute to the contact of the filaments with the components of vessel walls.
This is where one of the most serious consequences of the disease manifests—Cerebral Amyloid Angiopathy (CAA). This condition involves the deposition of beta-amyloid in the vessels and causes brain hemorrhages.
The cause of this structure's formation was also determined. The Flemish mutation removes one methyl group from beta-amyloid at residue 21. This change apparently promotes the formation of the Z-shaped folding. The researchers noted: 'Our results show how the loss of one methyl group at residue 21 leads to Aβ-folding with vascular tropism.'
There is an interesting aspect to this mechanism: previous studies demonstrated that beta-amyloid produced by the mutation has a lower tendency to aggregate in laboratory settings. Nevertheless, when deposits appear in the brain, the damage can be as intense as in traditional Alzheimer's disease.
In living organisms, the Flemish mutation causes the formation of the largest and most stable amyloid plaques observed in this disease. The interaction of these structures with blood vessels may help explain their potential to cause harm.
It is not yet clear exactly how this new structure contributes to brain destruction leading to dementia. Future research must investigate this mechanism in cellular and animal models.
Additional Information
Future studies must determine whether the Flemish folding alters the seeding, propagation, or neurotoxicity process in cellular or animal models. It is also necessary to establish whether similar structural principles occur in other hereditary or sporadic forms of Alzheimer's disease.
