Mutations in the prodomain of ADAM10 can cause Alzheimer's disease

Jaehong Suh, PhD
Massachusetts General Hospital (Charlestown, MA)


Rudolph Tanzi, PhD
Massachusetts General Hospital (Charlestown, MA)
Year Awarded:
Grant Duration:
April 1, 2010 to March 31, 2012
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern

Effect of Novel ADAM10 Gene Mutations in Alzheimer's Disease


In this study, we are exploring the idea that newly discovered Alzheimer's disease associated mutations in the Alzheimer's diseaseAM10 gene attenuate the function of ADAM10. This is being accomplished by generating and characterizing genetically modified mice over-expressing either wild-type or mutant forms of ADAM10. We are also assessing the effects of these mutations on Alzheimer's disease-like characteristics in a mouse model of the disease.


Alzheimer's disease is one of the leading causes of death and the most common form of dementia in the elderly. As the average life span is extended, the number of patients suffering from this disease is increasing dramatically, placing a huge burden on our healthcare system and on our global society. The incidence of Alzheimer's disease increases with age and doubles every five years after age 60. Currently there exists no effective treatment to stop or slow the progression of this devastating disease. Although an enormous amount of effort and resources have been devoted to research and clinical trials aimed at finding effective therapeutic interventions, the cause of this disease remains unclear. In this study we are attempting to validate our genetic findings from Alzheimer's disease families using a transgenic mouse model system. The novel mutations were found in the ADAM10 gene and can increase the production of neurotoxic peptide, called amyloid beta, which is considered a major factor for Alzheimer's disease progression. The results from this study can provide critical in vivo evidence for the cause of late-onset Alzheimer's disease. Moreover, the data emerging from this study would also serve as a firm foundation for the discovery and development of new drugs targeting ADAM10 for the treatment and prevention of Alzheimer's disease.

Research Updates

In a recent study, Dr. Suh’s team discovered two novel DNA mutations in the ADAM10 gene in several families with AD. The ADAM10 gene codes for a protein known as alpha-secretase, which cleaves the amyloid precursor protein (APP) in such a way that it prevents the generation of toxic peptide, called Abeta, which is the major component of senile plaques in the brains of AD patients. In this study, Dr. Suh’s team will characterize the ADAM10 mutations using mice engineered to have AD. The team has successfully generated several types of mice that overexpress either a healthy (wild-type) or a disease (mutant) form of the gene in their brains. Compared to the healthy controls, alpha-secretase activity in the brains of the mutant mice was found to be significantly decreased. Accordingly, when the team crossed each of these types of mice with an AD mouse engineered to hold a mutant form of APP, the mutant ADAM10 mice produced a significantly higher amount of Abeta and plaques in their brains. In cell based analysis, the team found that both the prodomain mutations impaired the ability of ADAM10 to properly fold (i.e. impaired the prodomain chaperone function). These results provide the first evidence in animals that support the idea that lack of alpha-secretase activity can be a cause of AD, and that up-regulation of ADAM10 is a potential therapeutic target for this devastating disease.


Suh, J., ROMANO D., TANZI, R.E. (2010) Late-onset Alzheimer's disease mutations in the ADAM10 prodomain impair non-amyloidogenic cleavage of the amyloid precursor protein in vivo. 40th Annual Meeting of Society for Neuroscience Program#/Poster#: 11.7

Suh, J., Im, D.S., Moon, G.J., Ryu, K.S., de Silva, R., Choi, I.S., Lees, A.J., Guénette, S.Y., Tanzi, R.E., Gwag, B.J. (2010) Hypoxic ischemia and proteasome dysfunction alter tau isoform ratio by inhibiting exon 10 splicing. J. Neurochem. 114:160-70. PubMed Icon Google Scholar Icon

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