Graduation Year

2015

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

David E. Kang, Ph.D.

Co-Major Professor

Allan Levey, Ph.D.

Committee Member

Dave E. Morgan, Ph.D.

Committee Member

Chad A. Dickey, Ph.D.

Committee Member

Yu Chen, Ph.D.

Committee Member

Kevin Nash, Ph.D.

Keywords

Alzheimer’s Disease, Amyloid β, Cofilin, Mitochondrial Dysfunction, RanBP9, Synaptic dysfunction

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by two major pathological hallmarks, amyloid plaques and neurofibrillary tangles. The accumulation of amyloid-β protein (Aβ) is an early event associated with synaptic and mitochondrial damage in AD. Therefore, molecular pathways underlying the neurotoxicity and generation of Aβ represent promising therapeutic targets for AD. Recent studies have shown that actin severing protein, Cofilin plays an important role in synaptic remodeling, mitochondrial dysfunction, and AD pathogenesis. However, whether Cofilin is an essential component of AD pathogenesis and how Aβ induced neurotoxicity impinges its signals to Cofilin are unclear.

In my dissertation studies, we found Aβ oligomers bind with intermediate activation conformers of β1-integrin to induce the loss of surface β1-integrin and activation of Cofilin via Slingshot homology-1 (SSH1) activation. Specifically, conditional loss of β1-integrin prevented Aβ induced Cofilin activation, and allosteric modulation or activation of β1-integrin significantly reduced Aβ binding to neurons and mitigated Aβ42-induced reactive oxygen species (ROS) generation, mitochondrial dysfunction, synaptic proteins depletion, and apoptosis. Furthermore, we found that SSH1 reduction, which mitigated Cofilin activation, prevented Aβ-induced mitochondrial Cofilin translocation and apoptosis, while AD brain mitochondria contained significantly increased activated/oxidized Cofilin. In mechanistic support in vivo, we demonstrated that APP transgenic mice brains contain decreased SSH/Cofilin and SSH1/14-3-3 complexes which indicates that SSH-Cofilin activation occurred by releasing of SSH from 14-3-3. We also showed that genetic reduction in Cofilin rescues APP/Aβ-induced synaptic protein loss and gliosis, as well as impairments in synaptic plasticity and contextual memory in vivo.

Our lab previously found that overexpression of the scaffolding protein RanBP9 increases Aβ production in cell lines and in transgenic mice, while promoting Cofilin activation and mitochondrial dysfunction. However, how endogenous RanBP9 activates cofilin and whether endogenous RanBP9 accelerates Aβ-induced deficits in synaptic plasticity, cofilin-dependent pathology, and cognitive impairments were unknown. In my dissertation studies, we found that endogenous RanBP9 positively regulates SSH1 levels and mediates A-induced translocation of Cofilin to mitochondria. Moreover, we demonstrated that endogenous RanBP9 mediates A-induced formation of Cofilin-actin rods in primary neurons. Endogenous level of RanBP9 was also required for Aβ-induced collapse of growth cones in immature neurons and depletion of synaptic proteins in mature neurons. In vivo, we also found APP transgenic mice exhibit significantly increased endogenous RanBP9 levels and that genetic reduction in RanBP9 rescued APP/Aβ-induced synaptic protein loss, gliosis, synaptic plasticity impairments, and contextual memory deficits. These findings indicated that endogenous RanBP9 not only promotes Aβ production but also meditate Aβ induced neurotoxicity via positively regulating SSH1. Taken together, these novel findings implicate essential involvement of β1-integrin–SSH1/RanBP9–Cofilin pathway in mitochondrial and synaptic dysfunction in AD pathogenesis.

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Neurosciences Commons

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