Effect Of Chronic Aluminum Exposure On CaM-CaMKⅡ-CREB And The Damage To Learning And Memory

PrefaceAluminum(Al) is the most abundant metal and the third common chemical element on earth.Aluminum chloride is an important coagulant used in water treatment and purification.Environmental exposure to Al is unavoidable because of its ubiquitous distribution;in humans,exposure is primarily via the diet with exposure levels dramatically increasing due to industrial activity and acid rain.The potential(neuro-) toxicity of Al has been debated and investigated for decades.It has been suggested that there is a relationship between high levels of Al and increased risk of a number of pathogenic disorders,such as microcytic anemia,osteomalacia.Moreover, Accumulating epidemiological studies regarding Al(â…¢) in drinking water show positive correlations to Alzheimer's disease.It is widely accepted that memory formation is dependent on changes in synaptic efficiency that permits strengthening of associations between neurons。Hippocampal synaptic plasticity,which includes LTP,has been suggested to be an important component of the cellular basis of learning and memory,There are more than 100 different molecules implicated in LTP induction and expression。The formation of LTP requires new protein synthesis,and protein synthesis must also dependent on the concentration of Ca²⁺,Ca²⁺entering the nerve cells combine with CaM,and further activate the downstream cascade,involved in the maintenance of LTP.CaM has at least two different conformations,apo CaM and Ca²⁺-CaM.CaM is particularly rich in mammalian central nervous system(CNS).As a regulatory protein,CaM play a role through its target,such as CaMKâ…¡etc.CaMKâ…¡'s expression level have a great relationship with CaMmRNA.Increased intracellular Ca²⁺ concentration combine with CaM,can activate CaMKâ…¡,activated CaMKâ…¡may effect autophosphorylation reaction.CREB belong to the downstream molecules of CaMKâ…¡.It attracted many researchers,because in the formation of LTP requires its existence.Ca²⁺-CaM-CaMKâ…¡-CREB is one of a series of a cascade in vivo,which play an important role in learning and memory.In this chapter,we focused on CaM,CaMK and CREB to study the effect of aluminum exposure on learning and memory,through molecular signal transduction experiments.Materials and methods1.Animal models30g Wistar rats after weaned were randomly divided into four groups,each group contains 10.Wistar rats were obtained from the Department of Laboratory Animals, China Medical University(CMU).The control group was fed with distilled water for 3 months.Al exposure group were fed with AlCl₃ diluted in distilled water for 3 months,the concentration was 0.2%,0.4%and 0.6%,respectively.The temperature in the breeding room were kept between 18℃and 23℃,the relative humidity were 45-55%.2.MethodsWestern blot detection of the expression level of CaM in rat hippocampal,the immunohistochemical method was used to measure the CaM,the mRNA expression levels were analyzed and quantified through reverse transcriptional PCR.Results1.The protein expression of CaM was compensatory increased by chronic aluminum exposure.2.CaM's quantity increased and colour was deep compared with the control group.3.The mRNA expression level of CaM and CREB in chronic aluminum groups was significantly increased and decreased respectively.DiscussionHippocampus is a key part of learning and memory,LTP(Long-term potertiation) is an important physiological model for researching the mechanism of learning and memory and is considered as the basis of learning and emory,.The increased calcium concentration the LTP induction and maintenance in presynaptic and postsynaptic neurons,especially the post-synaptic membrane of increased free Ca²⁺ concentration are one of the main conditions to the formation of LTP.Ca CaM CaMKCREB is one of important pathway in the the formation of LTP.Our results shown that:the CaM expression was increased,.It should be noted that chronic aluminum exposure in the rat hippocampus inhibits the expression of CaMK, then the CaM expression was compensatory increased.In Immunohistochemistry, CaM's quantity increased and colour was deep compared with the control group, showed that the expression of CaM indirectly increased by aluminum.In reverse transcriptional PCR,the mRNA expression level of CaM and CREB in chronic aluminum groups was significantly increased and decreased respectively.To sum up,Chronic aluminum caused some impact on learning and memory.with the increased concentration of aluminum,the damage are more obvious.Remind people that in our daily lives to minimize contact with the aluminum and prevent damage to people's learning and memoryConclusion1.Chronic aluminum through influencing the activity of CaMK lead to the expression of CaM compensatory increased.2.Because of aluminum intake,lead to the expression of CREB decreased.3.CREB as a CaMK's downstream molecule,impact on the formation of LTP and damage learning and memory ability eventually.