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2017 Grants - Rahim
PS1 FAD Mutants Affect NMDA-EphB Receptor Interactions and Neuroprotection
Md Al Rahim, Ph.D.
Icahn School of Medicine at Mount Sinai
New York, New York
2017 Alzheimer's Association Research Fellowship (AARF)
How do proteins in the brain interact to protect against damage that leads to Alzheimer's disease?
It has been proposed that Alzheimer's disease may develop as the brain loses the ability to protect itself against damaging events, such as inflammation, loss of blood flow, or overactivation of specific nerve cell pathways in the brain (excitotoxicity). The NMDA glutamate receptor, a protein in the brain, may interact with other proteins, called neurotrophins, to protect the brain from excitotoxic damage. Research has found that the neuroprotective effects of the NMDA glutamate receptor and neurotrophins depends on the protein presenilin 1 (PS1). Individuals with an inherited form of Alzheimer's disease (familial Alzheimer's disease) have a variant of the PS1 gene that has decreased activity. Though most individuals with Alzheimer's disease have a sporadic form of the disease rather than the inherited form, the pathologic changes that occur in the brain are the same in both forms of the disease. Thus, clarifying how PS1 is involved in neuroprotection by the NMDA glutamate receptor and neurotrophins may have important implications for developing novel treatments for Alzheimer's disease.
To examine how PS1 interacts with the NMDA glutamate receptor and neurotrophins to protect the brain against excitotoxicity, Md Al Rahim, Ph.D., and colleagues developed two types of mice that express variants of the PS1 gene and develop an Alzheimer's disease-like condition. They will use these mice to investigate how loss of PS1 function affects the physical interactions between various neurotrophin proteins involved in neuroprotection. They will also examine these interactions in human brain tissue from individuals who had familial Alzheimer's disease.
This study may help to define the proteins within the brain that are involved in neuroprotection against damaging events, such as overactivation of specific nerve cell pathways in the brain. New therapies that target these proteins may support neuroprotection and slow the progression of Alzheimer's disease.