The buildup of beta-amyloid plaques in the brain is not sufficient on its own to cause the death of neurons in Alzheimer’s disease, suggests a new study that challenges current views on how the disease progresses.
Researchers have widely believed that beta-amyloid drives nerve cell death in Alzheimer’s, but these results open up the possibility that other mechanisms could contribute to disease progression.
The study, “The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons,” was published in the journal Stem Cell Reports.
Accumulation of beta-amyloid plaques in the brain, one of the hallmarks of Alzheimer’s, occurs when a protein called the amyloid precursor protein (APP) is broken down, and its fragments, called beta-amyloid, clump together.
University of Queensland researchers used induced pluripotent stem cells (iPSCs) — adult cells capable of generating almost any cell in the body — from people with Down syndrome to better understand the role APP and amyloid plaques play in the death of nerve cells.
Those with Down syndrome, a condition in which a person is born with extra genetic material from chromosome 21, have a significantly increased risk of developing early-onset Alzheimer disease (before age 65). According to the Down Syndrome Society, about 30 percent of people with Down syndrome who are in their 50s have Alzheimer’s, while 50 percent or more will develop Alzheimer’s as they age.
The amyloid precursor protein gene is located in chromosome 21, the same one duplicated in Down syndrome.
“People with Down syndrome have an extra copy of chromosome 21, and therefore carry an extra copy of the amyloid precursor protein (APP) gene,” Dmitry A. Ovchinnikov, PhD, the study’s first author, said in a university press release.
Using a genome editing tool called CRISPR, researchers either deleted the extra copy of the APP gene in Down syndrome iPSCs or, inversely, increased the expression of the gene in normal stem cells. Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.
Using a specific cellular “cocktail,” they then transformed these stem cells into neurons and analyzed the effects of either deleting or increasing the APP gene.
Deleting the extra copy of the APP gene in Down syndrome cells normalized the levels of beta-amyloid plaques, while increasing APP expression had the opposite effect.
Surprisingly, however, higher levels of the APP gene in nerve cells were not synonymous with the death of these cells, and had no effect on promoting the accumulation of another toxic protein, called tau, whose buildup in nerve cells drives the progression of Alzheimer’s disease.
“Our data challenges the current dogma in the field that amyloid plaques are sufficient to cause neurodegenerative changes associated with Alzheimer’s disease,” said Ernst Wolvetang, PhD, the study’s lead author.
According to Wolvetang, these results could help develop more efficient therapies for Alzheimer’s, as well as reinforcing the idea of using stem cells to understand disease mechanisms.
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