메뉴 건너뛰기

대메뉴 건너뛰기 대메뉴 바로가기

Events

go to homeHOME  >  NEWS & EVENTS  >  EVENTS
[Seminar Notification] Dr. Goonho Park_01.25.2017
2017-01-18

1. Title : Aβ-induced synaptic toxicity via caspase cleavage of APP c-terminus.

2. Speaker : Goonho Park, Ph.D.

3. Affiliation : Postdoctoral fellow, ADRC scholar, Department of Neurosciences University of California, San Diego

4. Date : 01. 25. 2017

5. Place : SIMS Main Building, Auditorium 109 (1F)

6. Abstract :

In addition to senile plaques and neurofibrillary plaques, the two neuropathological hallmarks of Alzheimer’s disease (AD), synaptic loss is also characteristic of AD pathology and is believed to be a major contributor to cognitive impairment seen in this disorder. The mechanisms for synaptic injury and synapse loss in AD remain unclear. We hypothesize that caspase activation in neurons exposed to soluble oligomeric amyloid β-peptide (Aβ) may be one mechanism that underlies synaptic degeneration in AD. In our previous studies, we havefound that the amyloid precursor protein (APP) is a caspase substrate and there is an APP-dependent pathway of Aβ-induced toxicity that involves caspase-mediated cleavage of the APP C-terminus cleavage in position 664 (APP694 numbering). This resulted in the release of a putatively cytotoxic APP fragment, coined C31. However, to date, this pathway has not been carefully characterized in vivo. In this project, we examined a newly generated transgenic mouse line where the Asp at position 664 in the endogenous APP gene has beenreplaced by Ala in this knockin mouse line (APP D664A KI) to block caspase cleavage. Consequently, these mice allowed us to determine whether this mutation is protective against Aβ-induced synaptic toxicity. Treatment of organotypic slice cultures (OTSCs) from APP D664A mice with Aβ (7PA2 media) or by sindbis virus mediated infection of neurons provided the opportunity to investigate this APP-dependent pathway of Aβ-toxicity. Specifically, neuronal expression of C99ΔC construct, designed to produce only Aβ in neurons, was enable us to determine whether caspase activation is involved in synaptic spine loss at the single cell level. This application, therefore, was enable us to elucidate this C31-dependent pathogenic mechanism in vivo.