By combining genomic data and brain imaging data, scientists based at Case Western Reserve University School of Medicine have identified a previously unknown gene that appears to contribute to the formation of amyloid-β plaques, a process that drives Alzheimer’s disease (AD). The gene, called FAM222A, encodes a protein that is expressed at high levels in the brain—both in mice that serve as Alzheimer’s models, and in patients with AD. Because the protein interacts with amyloid-β protein and accumulates in amyloid-β deposits, the Case Western scientists believe that inhibiting the newfound protein’s interaction with amyloid-β could interfere with plaque formation, and thereby slow AD.

Details about the discovery of FAM22A appeared January 21 in the journal Nature Communications, in an article titled, “FAM222A encodes a protein which accumulates in plaques in Alzheimer’s disease.” Besides presenting evidence that the protein encoded by FAM22A occurs in amyloid-β plaques, the article describes how the protein attaches to amyloid-β peptide, as well as how increasing or decreasing the expression of the protein exacerbated or ameliorated plaque formation in mouse models.

“The protein encoded by FAM222A … accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation,” the article’s authors wrote. “Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model, whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation, and cognitive deficits in the AD mouse model.”

The Case Western scientists—led by Xinglong Wang, PhD, an associate professor of pathology, and Xiaofeng Zhu, PhD, a professor of population and quantitative health sciences—designated the FAM222A-encoded protein aggregatin. It consists of 452 amino acids, has a predicted molecular weight of 47 kD, and is remarkably immunoreactive within the center of amyloid-β plaques.

A fluorescence image of the aggregatin protein (red), that is, the protein encoded by the FAM22A gene, in the cortices of a patient with sporadic Alzheimer’s disease. Notice how aggregatin accumulates within the center of an amyloid plaque (green). [Case Western Reserve University]

“This protein characteristically accumulates, or aggregates, within the center of plaque in AD patients, like the yolk of an egg—which is part of the reason we named it aggregatin,” Wang said.

In the new work, the researchers began by correlating roughly a million genetic markers (called single-nucleotide polymorphisms, or SNPs) with brain images. They were able to identify a specific SNP in FAM222, a gene linked to different patterns of regional brain atrophy. Further experiments then suggested not only that the protein encoded by gene FAM222A is associated with AD patient-related amyloid-β plaques and regional brain atrophy, but also that aggregatin attaches to amyloid-β peptide, the major component of plaque, and facilitates the plaque formation.

“Based on the data we have, this protein can be an unrecognized new risk factor for Alzheimer’s disease,” Wang continued. “We also see this as a potential novel therapeutic target for this devastating disease.”

The relationship between Alzheimer’s (and subsequent brain atrophy) and amyloid plaques—the hard accumulations of beta-amyloid proteins that clump together between neurons in the brains of Alzheimer’s patients—has been well established among researchers. Less understood is precisely how, mechanistically, amyloid-β contributes to plaque formation. Further, while there has been much research into what genes might influence whether or not someone gets Alzheimer’s, there is less understanding of genes that might be linked to the progression of the disease, meaning the formation of plaque and subsequent atrophy in the brain.

Both amyloid-β formation and disease progression may be clarified now that aggregatin has emerged. Additional studies, however, will need to be undertaken.

“It is still unclear how aggregatin becomes accumulated within the center of plaques without the ability for self-aggregation,” the article’s authors noted. “As aggregatin protein levels were upregulated in AD, there may be a complex interplay among Aβ specific forms, aggregatin expression, post-translational modification, extracellular secretion, and other unknown factors.”

Regardless, the current findings indicate that reducing levels of aggregatin and inhibiting its interaction with amyloid-β peptide could be therapeutic—not necessarily to prevent Alzheimer’s but to slow its progression. “Our findings,” the authors of the Nature Communications article concluded, “not only inform future genetic studies of FAM222A, but also encourage detailed pathophysiological investigation of its encoded aggregatin for AD and related dementia.”

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