Columbia University researchers have discovered how variants of the ABCA7 gene, which are common among Black Americans, increase the risk for Alzheimer's disease.
The variants accelerate neurodegeneration by reducing the amount of neuropeptide Y, a protein essential for maintaining brain synapses and the resilience of brain neurons.
"Our findings not only enhance our understanding of Alzheimer's, but they also provide a new direction for developing treatments that could halt or reverse the progression of the disease," says study leader Caghan Kizil, PhD, associate professor of neurological sciences (in neurology and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at Columbia University Vagelos College of Physicians and Surgeons.
Why it matters
Variants in the ABCA7 gene were first linked to a greater risk of Alzheimer's about a decade ago, but it has been unclear how the variants advance the disease.
ABCA7 variants have been linked to greater Alzheimer's risk in many racial and ethnic groups but are particularly significant among Black Americans. ABCA7 variants are more strongly linked to Alzheimer's disease in Black Americans than the well-known APOE4 gene, the most influential Alzheimer's gene among white Americans.
Understanding the molecular underpinnings of genetic risk factors like ABCA7 is crucial for the development of new drugs.
Zebrafish as models for discovery
In the study, Kizil and his colleagues deleted one of two copies of the gene in zebrafish neurons (mimicking the gene's disruption in humans). Kizil's zebrafish allows his team to obtain information about Alzheimer's variants in weeks instead of months or years it can take with other animal models.
In the zebrafish, the researchers found that loss of the ABCA7 copy lowered the expression of neuropeptide Y in all regions of the brain but was most pronounced in the hippocampus, the brain's memory center.
"This disruption in neuropeptide Y levels impaired neurogenesis and reduced synaptic density, both of which are key factors in Alzheimer's pathology," Kizil says.
In human cells, the researchers found the same process in neurons derived from pluripotent stem cells and found signs that the protective neuropeptide Y pathway is compromised in the brains of people with Alzheimer's.
The researchers were able to rescue synaptic integrity in the zebrafish by restoring neuropeptide Y or other components in its pathway-highlighting a potential therapeutic target for Alzheimer's.
References
More information
The study, "ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling," was published Aug. 30 in Cell Genomics.
The other contributors (from Columbia unless noted): Huseyin Tayran, Elanur Yilmaz, Prabesh Bhattarai, Yuhao Min (Mayo Clinic Florida), Xue Wang (Mayo Clinic Florida), Yiyi Ma, Ni Wang (Mayo Clinic Florida), Inyoung Jeong (Norwegian University of Science and Technology), Nastasia Nelson, Nada Kassara, Mehmet Ilyas Cosacak (German Center for Neurodegenerative Diseases), Ruya Merve Dogru, Dolly Reyes-Dumeyer, Jakob Mørkved Stenerse (Norwegian University of Science and Technology), Joseph S. Reddy (Mayo Clinic Florida), Min Qiao, Delaney Flaherty, Tamil Iniyan Gunasekaran, Zikun Yang, Nathalie Jurisch-Yaksi (Norwegian University of Science and Technology), Andrew F. Teich, Takahisa Kanekiyo (Mayo Clinic Florida), Giuseppe Tosto, Badri N. Vardarajan, Ozkan Is (Mayo Clinic Florida), Nilüfer Ertekin-Taner (Mayo Clinic Florida), and Richard Mayeux.
This work was supported by the National Institute on Aging (R01AG067501, U24AG056270, RF1AG066107, U01AG046139, U19AG074879, and R01AG061796), a Columbia University Schaefer Research Scholar award, the Thompson Family Foundation Program for Accelerated Medicines Exploration in Alzheimer's Disease and Related Disorders of the Nervous System, Taub Institute grants for Emerging Research (TIGER), Toffler Scholar Program, Alzheimer's Association Zenith awards, and a FRIPRO research grant from the Research Council of Norway.
Caghan Kizil is a co-founder, shareholder, and scientific advisor of Neuron-D GmbH, which had no financial involvement in or influence on this study.
