Molecular changes of acetylcholinesterase and butyrylcholinesterase in Alzheimer patients during the natural couse of the disease and treatment with cholinesterase inhibitors : Insight into neurochemical mechanisms affecting the progression of the disease

摘要: Deficits in central cholinergic neurotransmission the brain correlate with cognitive impairment Alzheimer disease (AD) patients. This fact has resulted introduction of cholinesterase inhibitors (ChEIs) e.g. tacrine, donepezil, rivastigmine and galantamine, which are so far most successful therapeutic agents for symptomatic treatment AD The ChEIs principally act by inhibiting acetylcholinesterase (AChE), is primarily associated cells involved responsible inactivating acetylcholine at synapses peripheral nervous systems. neurobiological role butyrylcholinesterase (BuChE) not yet fully understood. Long-term clinical observations indicate that may, addition to cognitive, functional global improvement patients, have stabilizing effect on progression AD. turn implies may induce some changes gradually affect pathological processes disease. overall aim this thesis was characterize AChE BuChE, molecular, protein expression activity levels patients during natural course as well ChEIs, conjunction function Comparative analysis neurochemical findings cerebrospinal fluid (CSF) suggested globular (G) catalytic subunit variants their monomeric (G1), dimeric (G2), tetrameric (G4) molecular isoforms CNS neurons were likely major source CSF. found decrease time untreated whereas G2 isoform synaptic variant (AChE-S) unexpectedly increased. These reversed after ChEIs. bi-directional composition shown an impact suggesting different mechanisms adapted response controlling intrinsic stimulatory signals In particular, preferential distinct “readthrough” (AChE-R) observed both treated a consistent strong positive correlation support experimental data, ascribe putative neuroprotective AChE-R CNS. offer insight into underlying possible pseudoirreversible ChEI, cause sustained inhibition BuChE CSF reversible donepezil galantamine upregulated activity. A crucial clinically relevant question whether such increase reflects tolerance against long-term approached combination methodologies, showed elevated following vivo phenomenon. Attention be main domain improved optimal appeared prerequisite prevent deterioration Positive correlations also between several measures attention episodic memory suggest neuronal simultaneous enzymes advantageous. 3RVVHVVLRQ RI FHUWDLQ JHQHWLF YDULDQWV %X&K( DQG DSROLSRSURWHLQ ( 0 DOOHOH $SR( LQFUHDVHV WKH ULVN GHYHORSLQJ ODWH RQVHW $' SRLQWLQJ DW D SDWKRORJLFDO UROH thesis, majority high ZHUH IRXQG WR EH QRQ FDUULHUV ZKHUHDV PRVW WKRVH ZLWK PRGHUDWH ORZ &6) OHYHOV RQH RU WZR DOOHOHV 7KH SDWLHQWV KLJK level had score tests. addition, cerebral glucose utilization, assessed PET, positively correlated reduced CSF, particular PD\ KHQFH UHIOHFW DQ LQYHUVH UHODWLRQVKLS LWV GHSRVLWLRQ LQ EUDLQ regions, where much increased ascribed amyloid plaques. conclusion, these studies show selective occur transcription, alternative splicing inter-protein interactions or treatment, influence longterm efficacy therapeutics Different might useful differentiate responders from non-responders ChEI therapy. provide further understanding pharmacological features responses optimizing efficiency