The Role Of Melatonin In Ad Pathogenesis And Its Effect On Calcium Overload And Ad-related Genes

Alzheimer disease (AD) is a kind of neurodegenerative disease, Which is characterized with the memory losing in the aged. The morbidity of AD in the elder is only lower than that of angiocardiopathy and cancer. The pathogeny of AD is complicated, and the main aspects are included:(l) damage and aging of neurocyte;(2)inherent causes, some authentic AD related genes including Amyloid precursor protein(APP), Presenilin- 1 (PS-i), Presenilin-2(PS-2) and ApoE gene,(3)autoimmunity of nervous system. In the metaphase and anaphase of AD, the oxidative stress is obvious and outstanding, and the oxidative stress is an important and key physiopathologic process of AD. The depress of melatonin (MT) is regarded as an important cause of AD, which could explain the decrease of noradrenaline and serotonin and the increase of monoamine oxidase activity in the hippocampus of AD patients. Much attention was attracted to the foreground of MT in the therapeusis of AD, for MT is outstanding in these aspects:(1) easy to cross the blood-brain barrier ;(2) the most powerfiul free radical scavenger by far;(3) the potent lipotropic antioxidant;(4) inhibition of Alzheimer beta-fibrillogenesis. With the methods of hybridization in situ, laser scanning confocal microscope(LSCM), RT-PCR, radioimmunoassay , electron microscope and Morris water maze test, we observed the distribution of melatonin receptor Mel la and Mel lb in the CNS of adult rats and the changes of melatonin II rate-limiting enzyme arylalkylamine N-acetyltranferase (AANAT) expression during brain development and aging . And an AD model of rats were established according to the predecessor and confirmed further in behavior, tissue, peptide, molecule, ultrastructure, gene and second messenger level. The effect of melatonin of different dosage on the expression of AANAT and AD related genes such as APP, PS-i, P5-2 were observed in the CNS of AD rats.Tbe effect of melatonin on the free introcytoplasmic calcium [Ca2~]i level of hippocampus slice and isolated pyramidale neurons were also involved in our experiment. Our results were as follows: 1. Expression of melatonin receptor and its rat-limiting enzyme in the CNS of normal rats: time and space character (1) Distribution difference between Mel 1 a and Mel lb receptor mRNA in the CNS of normal adult rats (hybridization in situ research) @ Mel la mRNA-positive neurons-rich parts and nucleus of CNS were as follows: stratum pyramidale and denate gyrus of hippocampus, frontal and parietal lobe of cortex, supraoptic nucleus, paraventricular nucleus, suprachiasmatic nucleus, medial habenula2r nucleus, Purkinje cell layer and fastigial nucleus of cerebellar, anterior horn of the spinal cord, thalamostriate medulla, ventral lateral nucleus of thalamus, Lemniscus Lateralis, medial lemniscus, facial nerve nucleus, gigantocellular reticular nucleus, trigeminal nerve nucleus and striatum cortex etc. ?Mel lb mRNA-positive neurons-rich parts and nucleus of CNS were as follows: Purkinje cell layer of cerebellar, fastigial nucleus, global nucleus, emboliform nucleus of the medullaris cerebelli, stratum pyramidale and denate gyrus of hippocampus, frontal, parietal, occipital and temporal lobe of cortex, anterior horn of the spinal cord, supraoptic nucleus and suprachiasmatic nucleus. ?Mel 1 a mRNA-positive neurons were distributed very widely in CNS,...