Dendritic Spine Loss in Alzheimer Disease: Role of Caspase Cleavage of the Amyloid Precursor Protein (APP)

Goonho Park, PhD University of California, San Diego


Neurons communicate one another by forming synapses in brain. For reasons that are not completely clear, these synaptic connections are susceptible to damage and are lost in the early stages of AD. Injury and loss of synapses in the brain are believed to be a major reason for cognitive impairment seen in individuals with AD.  Amyloid-beta peptide (Aβ), which is generated from amyloid precursor protein (APP), is hypothesized to be one of the major reasons for synaptic damage.  In addition, however, APP also generates another fragment called C31 which we hypothesize could play an additional role in synaptic injury.  In this project, we will test whether blocking C31’s generation from APP can protect synapses from injury and damage.  

Project Details

With aging, overall brain function is declining; with Alzheimer’s and other neurodegenerative diseases, patients are also losing their most cherished memories. Through my research, I hope to explain the underlying mechanism behind the aging of the brain and neuronal death. Of several theories to explain the pathomechanism of Alzheimer’s disease (AD), the amyloid cascade hypothesis currently guides our understanding; however, interventions suggested by this framework have thus far all failed to be clinically effective. Therefore, we still need to know more details about AD’s pathomechanism. Our study will look at the toxicity of amyloid beta (Aβ) and the other amyloid precursor protein (APP)-derived fragments, an area that has been difficult to thoroughly understand because of the lack of successful purification of some of the peptide fragments. In this study, we will genetically explore a modified mouse model and a novel virus system expressing Aβ in order to determine the correlation between the APP fragmentation and AD. I hope that designing effective therapeutics for AD may be made more precise by this investigation.