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Integrative Approach Identifies an APOE4-dependent Pathway to Alzheimer's Disease

NEW YORK (GenomeWeb News) – By combining systems biology and cell biology approaches, Columbia University researchers identified a molecular pathway that connects an APOE gene variant to the development of late-onset Alzheimer's disease, they reported in the online edition of Nature today.

While the genetic roots of familial, early-onset Alzheimer's disease have been linked to specific mutations, the genetic underpinnings of the late-onset form of the disease have been more difficult to tie down. The APOE4 variant, though, is a known risk factor for the disease; people who are heterozygote for the APOE4 variant have a three-fold increase in LOAD risk, while homozygotes for the variant have a 10-fold increase in disease risk.

Using whole-transcriptome analysis of healthy APOE4 carriers, healthy APOE4-negative people, and people with late-onset AD, followed by cell biology experiments, the researchers homed in on candidate core regulatory mediators of a network that leads to late-onset AD.

Two of those regulators seem to have roles in amyloid beta production and amyloid beta A4 precursor protein, or APP, processing. Amyloid beta, the researchers noted, is the main component of the amyloid plaques that characterize the disease.

"[O]ur findings reveal an APOE4-dependent molecular pathway to [late-onset] AD and LOAD risk," Asa Abeliovich and his colleagues wrote.

Abeliovich is the leader on the Nature study and an associate professor of pathology and cell biology and of neurology at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at the Columbia University Medical Center.

He added in a statement that the two regulators —SV2A and RFN219 — could represent possible targets for therapeutics. "What's exciting to us is that these approaches may play a role in the development of drugs for the common non-familial form of Alzheimer's disease," he said. "This has been an enormous challenge."

Through a transcriptomic study of cerebral autopsy brain tissue from 185 healthy APOE4-positive and -negative people, the researchers found that gene expression patterns in the brains of people with the high-risk phenotype were similar to those found in LOAD brains. Indeed, 215 of 8,449 gene transcripts were altered in APOE4-positive or LOAD brains in the same direction while 37 were altered in opposite directions. Gene expression patterns linked to aging, however, overlapped with LOAD patterns, though not with APOE status.

In addition, in a separate set of cortical tissues, they found that this APOE4/LOAD pattern was correlated with changes that occur during the transition from unaffected, LOAD-free tissue to incipient-LOAD tissue.

"These data indicate that the APOE4 status of an individual reflects a pro¬dromal, or 'primed', state for developing LOAD," noted Vivek Swarup and Daniel Geschwind from the David Geffen School of Medicine at the University of California, Los Angeles, in a related Nature commentary.

To look at network-level changes, Abeliovich and his colleagues turned to a differential co-expression analysis, or DCA, approach that separates out causative changes from secondary gene expression changes.

They applied this DCA approach to the APOE4/LOAD gene expression pattern to rank candidate node elements. Among the top 20 candidate node elements were a number of genes, including SVA2, which had previously been linked to APP processing and sorting.

The top-ranked hit, RNF219, had not been previously linked to LOAD, though variants at that locus had been associated with changes to lipid metabolism, cognitive performance, and central nervous system ventricle volume.

Through a number of in vitro experiments, Abeliovich and his colleagues validated those candidate node genes, with a particular focus on SVA2 and RNF219. For example, they noted that in cell lines, both SVA2 and RNF219 modulate APP processing. SVA2, they added, appears to regulate APP processing through endocytosis and intracellular trafficking, while RNF219 is a nuclear regulatory mediator of APP endocytosis and processing.

In addition, they found that treating APOE4-positive neuronal cell lines with levetiracetam, a SV2A inhibitor that is used to treat seizure disorders, led to lower levels of amyloid beta production.

They also turned to sets of previously published genome-wide association data to find that SNP variants at RNF219, as well as at FYN, were linked to age of disease onset in LOAD.

And by drawing on publicly available positron emission tomography imaging of the brains of 206 unaffected elderly individuals whose genotype had been determined, the researchers found that APOE4 carrier status, as well as an RNF219 minor allele, was associated with increased amyloid beta amyloid load throughout different parts of the brain.

"Taken together, our findings reveal an APOE4-dependent molecular pathway to LOAD and LOAD risk," the researchers wrote.

That pathway offers up possible targets for treatments, the researchers noted.

"The identification of key regulatory molecules and pathways involved in APOE-based risk for LOAD sets the stage for investigating their link to other deficits in this disorder," Swarup and Geschwind added in their commentary. "Ultimately, such inves¬tigations should lead to molecularly targeted therapeutics."

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