Investigating KCC2 activity in Amyloid Precursor Protein (APP) associated Alzheimer’s Disease

One of the hallmarks of AD is the formation of sticky protein clumps in the brain known as amyloid-beta (Aβ) plaques, which are formed from specific fragments of the amyloid precursor protein (APP). The intact form of APP is essential for synaptic function; however, much remains to be explored regarding the impact of APP processing on the pathophysiology of AD. Recent evidence suggests that APP can affect neuronal activity through protein-protein interactions with the potassium-chloride cotransporter 2 (KCC2), a protein whose function is essential for healthy electrical activity in the brain. Thus, this thesis used a variety of techniques to investigate KCC2 activity in APP-associated AD. Chapter 3 established the APP-KCC2 interaction, and the expression levels and alterations of these proteins affect the physiological expression and regulation of each other. In addition, this chapter suggests that APP expression and regulation may have consequential effects on key proteins involved in the regulatory pathways for KCC2 activity, and vice versa. In support of the in vitro and ex vivo findings, Chapter 4 integrates in silico techniques to provide a comprehensive view of the molecular interactions between APP and KCC2, thereby shedding light on the participating residues and their molecular behaviours. Chapter 5 provides supporting evidence for ZT-1a as a potential inhibitor of kinases associated with the signalling pathway that inhibits KCC2 activity. Additionally, ZT-1a modulates the expression and phosphorylation of the APP and Tau proteins. Collectively, this thesis establishes the interaction between APP and KCC2, demonstrating that the expression/regulation of one impacts that of the other. This thesis also suggests that ZT-1a may be involved in modulating pathways that regulate both APP and KCC2. Thus, further investigation could yield novel ideas for exploring multidirectional therapeutic strategies to manage APP-associated AD with ZT-1a.<p></p>

Author dc:creator

• Sunday Josiah (21040571)

• Amyloid Precursor Protein
• Alzheimer’s Disease
• KCC2
• ZT-1a
• Tau protein
• WNK-SPAK kinases

Statement dc:rights

• All rights reserved
• Open Access after 2027-07-17

Identifier

10779/exe.31081795.v1

OAI identifier oai:identifier

oai:figshare.com:article/31081795