2010 Pilot Projects

Description

The investigators will conduct two studies in parallel: a mouse study to determine the longitudinal growth of amyloid plaques in transgenic mice and a human study to determine the acute effects of antidepressants in human CSF. Dr. Sheline and her co-investigators have demonstrated that antidepressants lower amyloid production in mouse brain in transgenic mice. They now extend the study to determine the effect on amyloid plaque accumulation. In addition they will gather preliminary data on antidepressant effects on human CSF amyloid, a marker of Alzheimer’s disease.

Grants and Awards

“Citalopram Decreases Amyloid-B Synthesis in Human CSF”
NIH-NINDS, R21AG0390690-01A1 (PI, Sheline)
This project will determine whether compared to placebo, SSRI antidepressants lower the production of Aβ in human CSF.

“Citalopram decreases CSF Aβ: a randomized dose finding trial”
NIH-NINDS, R01AG041502-01A1 (PI, Sheline)

“Synaptic regulation of ERK-mediated amyloid-β metabolism”
NIH-NINDS, R01AG042513 (PI, Cirrito)

Publications

Cirrito JR, DiSabato BM, Restivo JL, Verges DK, Goebel WD, Sathyan A, Hayreh D, D’Angelo G, Benzinger T, Yoon H, Kim J, Morris JC, Mintun MA, Sheline YI. Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans. PNAS, 108:14968-73 (2011).

Sheline YI, West T, Yarasheski K, Swarm R, Jasielec MS, Fisher JR, Ficker WD, Yan P, Xiong C, Frederiksen C, Grzelak MV, Chott R, Bateman RJ, Morris JC, Mintun MA, Lee JM, Cirrito JR.  An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice. Sci Transl Med, 10.1126/scitranslmed.3008169 (2014).

Jonathan R. Fisher, Clare E. Wallace, Danielle L. Tripoli, Yvette I. Sheline and John R. Cirrito. Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo. Mol Neurodegener. 2016 Jun 18;11(1):45.

Updated January 2019

Description

In this project the investigators try to identify the genetic cause of a rare early-onset dementia disease in a family. This disease is characterized by gradual onset, progressive course, and deficits in episodic memory, executive function, and visuospatial abilities. The hereditability pattern of the disease suggests that the disease is caused by a genetic mutation. Dr. Cruchaga and Dr. Sands plan to take advantage of the last sequencing technologies to identify the genetic cause of the disease. Then, they will generate cellular models to understand the pathogenic mechanism implicated in this disease. This project will allow the development of genetic test and the identification of potential therapeutic targets.

Publications

Benitez B, Alvarado D, Cai Y, Mayo K, Chakraverty S, Norton J, Morris JC, Sands MS, Goate A, Cruchaga C. Exome-sequencing confirms DNAJC5 mutations as cause of Adult Neuronal Ceroid-Lipofuscinosis. PLoS One, 6(11):e26741, (2011).

Updated June 2017

Description

The investigators use a new technique, known as next-generation DNA sequencing, to identify the genetic causes of blindness in several patients. Dr. Corbo and the co-investigators will utilize a novel computational strategy which permits them to sift through these large next-generation sequencing datasets and find the cause of disease much more readily than was previously possible. Not only will these studies improve our ability to identify the cause of blindness in individual patients, but they will lay the groundwork for applying this same strategy to other neurodegenerative diseases in the future.

Publications

Ozgül RK, Siemiatkowska AM, Yücel D, Myers CA, Collin RW, Zonneveld MN, Beryozkin A, Banin E, Hoyng CB, van den Born LI; European Retinal Disease Consortium, Bose R, Shen W, Sharon D, Cremers FP, Klevering BJ, den Hollander AI, Corbo JC. Exome Sequencing and cis-Regulatory Mapping Identify Mutations in MAK, a Gene Encoding a Regulator of Ciliary Length, as a Cause of Retinitis Pigmentosa. Am J Hum Genet, 89(2):253-64, (2011).

Updated January 2019

Description

Huntington Disease (HD) is an incurable neurodegenerative disease. There are no effective therapies. Further, in general, little is known about molecular mechanisms that might be targeted to block the misfolding and aggregation of the mutant huntingtin protein, which is the cause of the disorder. The Diamond laboratory previously identified a lead compound that blocks pathology in cells and animal models of HD. This grant will directly test the presumed mechanism of this compound, which involves the interaction of a ubiquitous cellular protein (profilin) with the huntingtin protein. The experiments proposed will determine exactly how profilin interacts with huntingtin to block huntingtin’s pathological aggregation, and what are the consequences of this interaction for the structure of huntingtin. This work will elucidate the precise molecular mechanism of the lead compound, and could lead to a better understanding of how to treat HD.

Grants and Awards

See also, Huntington’s Disease target of $4.5 million in NIH grants.

Updated June 2017