Exploring the putative calbindin-D28k and caspase-3 interaction Year 2 Grant uri icon

abstract

  • Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by the onset of neurocognitive symptoms and affects more than 35 million individuals worldwide, including ~6 million people in the United States. There are two main pathological features in brain tissue of those who suffer from AD: extracellular insoluble senile plaques, formed by the improper cleavage of amyloid-? (A?) peptide and intraneuronal neurofibrillary tangles formed by the hyperphosphorylated tau protein ((p)tau). Accrual of each in the brain often serves as a defining indicator of the disease. Caspase-3 is a potent and essential protein required for apoptosis and has been linked to A? and intraneuronal neurofibrillary tangles. On the other hand, Calbindin-D28k (D28k) has been shown to have neuroprotective effects against AD. Caspase-3 is a potential therapeutic target to prevent or delay the onset of AD, and drug development has focused on developing peptide-based inhibitors to block the caspase-3 active site. If D28k does bind caspase-3, drugs designed to mimic D28k could protect neurons from AD pathologies, but first we must definitively confirm if the two proteins directly interact. We propose to unequivocally determine if D28k binds caspase-3 using a wide range of biochemical and structural techniques. Our work will establish if D28k could be the basis for anti-caspase-3 AD drugs or if the field needs to change directions and focus on more promising targets.

date/time interval

  • June 2024 - December 2024