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Reduced hippocampal MT 2 melatonin receptor expression in Alzheimer ’ s disease

The pineal secretory product melatonin provides a circadian and seasonal signal in vertebrates regulating responses to changes in day length [1–3]. The biological clock in the suprachiasmatic nucleus (SCN), entrained by the light-dark cycle, controls the rhythm of melatonin synthesis in the pineal gland with the highest levels of melatonin production occurring during the night [1–5]. Melatonin provides a hormonal signal of darkness. The physiological effects of melatonin include retinal [6], antioxidative [7], neuroprotective [8, 9], vasoactive [10–12], immunological [13] and oncostatic [14] properties. In mammals melatonin acts through two specific highaffinity membrane receptors, MT1 (previously termed Mel1a) and MT2 (previously termed Mel1b), which have been cloned and characterized [15–18]. They share a common seven-transmembrane structure and transduce signals via G protein-coupling. Whereas MT1 is coupled to different G proteins that mediate adenylyl cyclase inhibition and phospholipase Cb activation, MT2 is also coupled to inhibition of adenylyl cyclase and additionally inhibits cyclic GMP levels via the soluble guanylyl cyclase pathway [5, 19]. A third melatonin receptor, Mel1c, was cloned from Xenopus [20] and birds [21] but is not found in mammals, so that of the family of three melatonin receptor subtypes in vertebrates, only two are present in mammals [5]. MT1 mRNA distribution has been studied in different mammalian brains including rodents [22] and humans [23, 24]. In human central nervous system (CNS) MT1 mRNA is expressed in SCN [23], cerebellum, occipital, parietal, frontal and temporal cortex, thalamus and hippocampus [24]. There is also immunohistochemical evidence for the presence of MT1 in human hippocampus [24], cerebrovascular tissue [11] and retina [25]. The presence of MT2 mRNA in CNS, on the other hand, has been shown in rodent SCN using in situ hybridization [26] and quantitative receptor autoradiography [27]. Thus far, in the human CNS, MT2 mRNA has been found in the cerebellum [28], and RT-PCR revealed MT2 expression in the hippocampus [15]. However, the exact cellular distribution of MT2 in human CNS is still not known. As specific antibodies against MT2 have been developed recently [29], we studied MT2 distribution in human hippocampus using immunohistochemistry. The results were compared with findings in the hippocampus of Alzheimer’s disease (AD) patients, because melatonin alterations may contribute to AD symptomatology and pathology, and hippocampus is a brain region highly implicated in AD-related neurodegeneration [3, 8, 9]. This study provides the first immunohistochemical description of MT2 distribution in human hippocampus and provides evidence for altered expression of MT2 in patients affected with AD.