The investigation of the neuronal and synaptic defects in early stage of amyloid-beta pathology

Yook, Yeeun

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https://hdl.handle.net/2142/124674 Copy

Description

Title

The investigation of the neuronal and synaptic defects in early stage of amyloid-beta pathology

Author(s)

Yook, Yeeun

Issue Date

2024-04-24

Director of Research (if dissertation) or Advisor (if thesis)

Tsai, Nien-Pei

Doctoral Committee Chair(s)

Tsai, Nien-Pei

Committee Member(s)

• Ceman, Stephanie S
• Chung, Hee Jung
• Christian-Hinman, Catherine A

Department of Study

Molecular & Integrative Physl

Discipline

Molecular & Integrative Physi

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Amyloid-beta
• hyperexcitability
• seizures
• PSD-95
• APP/PS1

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive loss of neural cells and subsequent cognitive dysfunction, making it the primary cause of dementia. Previous studies have predominantly focused on brain hypoactivity caused by the toxic aggregation of amyloid beta (A) plaques and neurofibrillary tangles so far. However, emerging evidence suggests that hyperexcitability precedes other symptoms by decades in patients and further accelerates the disease progression. Interestingly, treatment with an antiepileptic drug, levetiracetam, has shown promise in slowing down cognitive decline in both patients and mouse models, indicating potential therapeutic benefits. Nevertheless, this paradigm shift still requires further investigation into the molecular basis behind the initiation of hyperexcitability in the preclinical stage and its transition to hypoactivity to develop therapeutic approaches for AD. We hypothesized that A accumulation may drive hyperexcitability in the early pathology because A starts deposition without tauopathy at this stage. As demonstrated in Chapter 2, our study elucidates the molecular mechanism by which A elevates postsynaptic density protein 95 (PSD-95), promoting seizure response in young APP/PS1 mice. This elevation results from reduced ubiquitination caused by Akt-dependent phosphorylation of E3 ubiquitin ligase murine-double-minute 2 (Mdm2). PSD-95 is required for facilitating excitatory synapses and the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors induced by Aβ. Inhibition of PSD-95 corrects these Aβ-induced synaptic defects and alleviates seizure activity in APP/PS1 mice, underscoring its potential as an early biomarker and novel therapeutic target for AD. Excitotoxicity, induced by prolonged excitation, leads to neuronal damage and death, potentially contributing to the transition from hyper- to hypoactivity in AD. This process activates activating transcription factor 4 (ATF4), a molecular switch between pro-survival and pro-death pathways, whose upregulation in AD patients and mouse models suggests its involvement in this transition. In Chapter 3, we characterize the role of ATF4 in neuronal network activity and mouse behaviors, finding that ATF4+/- neurons exhibit reduced spontaneous spike rate, burst frequency, and synchronicity. These changes correlate with memory impairment rather than seizure severity, highlighting ATF4 as a necessary component in learning and memory performance. This suggests the potential role of ATF4 in learning and memory impairment in AD, warranting further research. Taken together, this dissertation offers novel insights into early AD pathology, highlighting the roles of PSD-95 and ATF4, thereby paving the way for innovative therapeutic strategies.

Graduation Semester

2024-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2024 Yeeun Yook

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