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Study identifies new link between Down syndrome and Alzheimer’s disease.

Down syndrome (DS) results from the trisomy of chromosome 21 in humans and is the most common cause of genetically defined intellectual disability. Among the various triplicate genes in DS is the one encoding for Ab precursor protein (APP), a transmembrane glycoprotein known for its association with the pathogenesis of Alzheimer disease (AD). This means that individuals with Down syndrome who survive into adulthood face the additional challenge of early-onset dementia, in which toxic amyloid plaques build up in the brain.

It is known that APP is cleaved by the sequential proteolytic activity of the b -secretase and the c-secretase complex, which ultimately is responsible for the formation of the Ab peptides. Because activation of the c-secretase complex is the required final step for the formation of Amyloid beta, in recent years there has been a tremendous effort to develop drugs that block this complex activity as a disease-modifying therapeutic approach to lowering Ab levels. The c-secretase activating protein (GSAP) is a newly recognized protein which acts as a rate-limiting step in Ab formation. Now, a study from researchers at Temple University has shown that dementia in Down syndrome involves defects in a regulatory enzyme known as γ-secretase activating protein (GSAP), which also malfunctions in Alzheimer’s disease. The team state that the work could soon lead to the development of a specific GSAP-targeted therapy that is capable of safely mitigating dementia in Down syndrome. The study is published in the journal Annals of Neurology.

Previous studies show that in Down syndrome, APP overexpression is extreme, reaching levels in the brain that are four to five times higher than normal. Its excess levels are a direct consequence of the triplicate copy of the 21st chromosome, which causes the syndrome and houses the APP gene. 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. Recent evidence suggests that GSAP is increased in postmortem brain tissues of AD patients, and its pharmacological or genetic inhibition results in an amelioration of the AD-like amyloidotic phenotype in transgenic mouse models of the disease. However, no data are available on this protein in DS. Considering the similarity between AD and DS regarding the high levels and deposition of Ab peptides, the current study investigated if this pathway could also be altered in brain tissues of DS patients.

The current study examined donated tissue from the brains of deceased Down syndrome patients. Results show that when compared to postmortem brain tissue from healthy subjects, samples from individuals with Down syndrome had substantial elevated levels of both GSAP protein and its activity.  Data findings show that GSAP hyperactivity was associated with abnormalities in the GATA1 transcription factor, which controls GSAP production.

Results show that when GATA1 activity was silenced in neurons that overexpressed APP, both GSAP levels and amyloid beta peptide levels increased; with overexpression of GATA1 producing the opposite effect.  The group state that to their knowledge this is the first study to draw a connection between GSAP hyperactivity and excess processing of the Aβ precursor protein (APP), the protein responsible for the final formation of amyloid beta, in Down syndrome.

The team surmise that these findings could mark a turning point for Down syndrome survivors.  They go on to add that their study shows 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.  For the future, the researchers state that they already have access to a GSAP inhibitor. They now plan to investigate the efficacy of the agent in preclinical studies, moving onto a clinical trial, where they hope to be able to reduce amyloid production safely and effectively.

Source: Lewis Katz School of Medicine at Temple University (LKSOM)

© 2015 David Goodsell & RCSB Protein Data Bank

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