INVESTIGATIONS OF BETA-AMYLOID AND ALPHA-SYNUCLEIN ASSOCIATED NEUROCHEMICAL ALTERATIONS IN LEWY BODY DEMENTIAS

Abstract

Lewy body dementias (LBD), encompassing the clinical subtypes of Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), are the second most common cause of neurodegenerative dementia. Limited studies have investigated the pathological mechanisms, whilst potential therapeutic or disease-modifying targets remain an unmet need. In this thesis, we examined β-amyloid (Aβ) and α-synuclein associated neurochemical alterations in postmortem neocortex samples and investigated potential mechanisms for abnormal α-synuclein phosphorylation with an in vitro model. We found that α-synuclein phosphorylation at Ser129 and collapsin mediator response protein-2 (CRMP2) phosphorylation at Thr514 were significantly elevated in DLB, correlating with Aβ burden and synaptic pathologies, suggesting that these may be Aβ- and/or α-synuclein targeting therapeutic targets in DLB. Furthermore, pinocembrin could inhibit the increase of pSer129 α-synuclein and restore mitochondrial function in an MPP+ lesioned model, indicating the potential usage of pinocembrin as a therapeutic strategy in LBD.