Link discovered between Down syndrome dementia and Alzheimer's disease

By John Murphy, MDLinx
Published November 4, 2015

Key Takeaways

Researchers have discovered that dementia in Down syndrome involves defects in a regulatory enzyme that also malfunctions in Alzheimer’s disease. This discovery could soon translate into a targeted therapy to inhibit dementia in Down syndrome, the researchers predicted. Their findings were published online October 29, 2015 in Annals of Neurology.

People with Down syndrome have an extra copy of the amyloid beta precursor protein (APP) gene on chromosome 21, which leads to early-onset Alzheimer’s disease-like symptoms. This is the latest in recent studies linking a connection between a patient's pre-existing condition to Alzheimer's disease.

“The higher levels of APP in Down syndrome patients causes increased formation of amyloid beta peptides, which then precipitate in the amyloid plaques in the brain much earlier in life,” said senior investigator Domenico Praticò, MD, Professor in the Departments of Pharmacology and Microbiology and the Center for Translational Medicine at the Lewis Katz School of Medicine at Temple University, in Philadelphia, PA.

Amyloid plaques can form as early as the late teens and early 20s in people with Down syndrome, and symptoms of dementia follow in the ensuing years.

In this study, Dr. Praticò and colleagues determined that γ-secretase activating protein (GSAP), a regulatory enzyme implicated in amyloidogenesis in AD, is also elevated in people with Down syndrome.

The researchers also found that GSAP hyperactivity is associated with abnormalities in the GATA1 transcription factor, which controls GSAP production. They demonstrated that when GATA1 activity was silenced in neurons that overexpressed APP, both GSAP levels and amyloid beta peptide levels increased. When the researchers overexpressed GATA1, GSAP levels and amyloid beta peptide levels decreased.

These are meaningful findings for people with Down syndrome because GSAP inhibitors are already available.

“We've shown that GSAP inhibition reduces amyloid production, and because GSAP is specific to the formation of amyloid, without affecting other pathways, it should be a safe alternative to other strategies of a direct γ-secretase inhibition,” Dr. Praticò said.

The researchers are now planning to investigate the effects of such an agent in preclinical studies in mice. “We are very optimistic that our animal models will work,” Dr. Praticò said. “If they do, we will move to a clinical trial, where we hope to be able to reduce amyloid production safely and effectively.”

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