ACTIVITY-INDUCIBLE KINASE PLK2 REGULATES APP AMYLOIDOGENIC PROCESSING AND Aβ MEDIATED SYNAPTIC DEPRESSION
Creator
Lee, YeunKum
Advisor
Wolfe, Barry B
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cognitive deficits. Amyloidogenic processing of amyloid precursor protein (APP) produces Aβ peptides, the major component of hallmark AD senile plaques. Synaptic activity stimulates Aβ production, and Aβ promotes synaptic depression, suggesting Aβ mediates homeostatic plasticity of excitatory synapses. However, mechanisms linking synaptic activity to Aβ production are unclear. I demonstrate that Plk2, an activity–inducible homeostatic downregulator of excitatory synapses, is critical for activity–mediated Aβ production. Plk2 directly binds and phosphorylates APP in vitro and associates with APP in vivo. Plk2 specifically accelerates APP amyloidogenic cleavage pathway and is required for stimulated Aβ secretion by elevated synaptic activity. Phosphorylation sites at T668 and S675 are required for Plk2– and activity–induced synaptic depression via loss of GluA2 type AMPA receptors. Furthermore, increased Plk2 levels were detected in the brains of AD mouse model APP–SwDI, and genetic perturbation of Plk2 reduced amyloid plaque formation in APP–SwDI hippocampus. Together, these findings demonstrate that heightened synaptic activity promotes APP amyloidogenic processing and Aβ production via Plk2.
Description
Ph.D.
Permanent Link
http://hdl.handle.net/10822/557740Date Published
2012Subject
Type
Publisher
Georgetown University
Extent
115 leaves
Collections
Metadata
Show full item recordRelated items
Showing items related by title, author, creator and subject.
-
ACTIVITY-DEPENDENT REGULATION OF AMYLOID PRECURSOR PROTEIN (APP) BY POLO-LIKE KINASE 2 (PLK2): NOVEL ROLES IN SYNAPTIC PLASTICITY
Lee, Ji Soo (Georgetown University, 2016)The brain uses a special feature, synaptic plasticity, for learning and memory. As forms of synaptic plasticity, associative plasticity, long-term potentiation (LTP) and long-term depression (LTD), is a positive feedback ...