Cordycepin Prevents Cognitive Impairments Induced By Aβ

Alzheimer’s disease（AD）is a common neurodegenerative disease associated with progressive deterioration of cognition and memory in elderly people,accompanied with many neuropathological hallmarks such as Amyloidβpeptide accumulation,progressive neuronal and prominent synaptic loss and a specific reduction of cholinergic neurons.Among them,the main clinical symptoms of AD are the cognition function,behavior and mood barrier.With the aggravation of the aging of the social population,the number of AD cases increases gradually.It is predicted that by 2050,the number of people suffering from dementia will reach 152 million,more than triple from the currently accounts for 50 million cases.However,drug therapy for this dreadful ailment is still in its infancy and fails to delay the progression of the disease,which may lead to the heavy burden on the families and the society.Overexpression of Aβin the brain is always recognized as one of the main factors in AD pathogenesis,which may disrupt the cholinergic nervous system,and cause neurotoxicity,irreversible brain tissue damage,and synaptic dysfunction.It has been shown that the Aβ_25-35fragment retained most of the physical and biological characteristics of the full-length Aβpeptide.Moreover,accumulating evidences had shown that learning and memory was significantly impaired by intrahippocampal amyloidβ,especially levels of soluble Aβcould abolish hippocampal long-term potentiation.D-galactose could cause metabolic disorder,increase the level of free radicals and accelerate the aging of immune organs,ultimately result in degenerative process.Many features of subacute aging induced by D-galactose have been recognized as similar to those in naturally aged mice and rats.Thus,the model,which was established by intraperitoneal injection of D-galactose combined with microinjection of Aβ_25-35in the hippocampus due to its feasibility,could simulate the dementia symptoms similar to the aging pathological environment in AD patients.Cordyceps militaris is a valuable traditional Chinese medicine.As a characteristic component of cordyceps militaris,cordycepin（known as 3-deoxyadenosine,CRD）demonstrated various pharmacologic actions,including inhibition of tumor,modulation of the immunity and suppression of inflammation,antioxidant activities and antiaging.Recently,a great deal of evidences have demonstrated that cordycepin can modulate neuroprotective effects on the central nervous system（CNS）.Moreover,cordycepin could significantly decrease the neuronal loss and memory impairment induced by ischemia,Aβ-induced toxicity and the hypoxic insult-induced impairments.Nevertheless,the exact neuroprotective effect and its underlying mechanism of cordycepin on cognitive impairments of AD remain unknown.Considering it has been previously demonstrated that the beneficial effect of cordycepin or cordyceps militaris extracts in different models of cognitive deficits.Therefore,the behavioural test,biochemical detection,HE tissue staining,field excitatory postsynaptic potentials（f EPSPs）recordings and single cell recording were used to study the mechanisms underlying the protective effect of cordycepin on cognitive impairments of AD.1.Cordycepin ameliorates cognitive impairments induced by Aβcombined with D-galactos.Intraperitoneal injection of D-galactose combined with microinjection of Aβ_25-35in hippocampus were used to establish the AD model.The cognitive ability was evaluated by Y maze test,and the potential mechanisms were determined by the enzymatic activity of ACh E and the neuronal morphology analysis respectively.The cognitive ability of AD rats was significantly impaired when compared with control group,as well as the acetylcholinesterase（Ach E）activity increased evidently and neurons damaged seriously.Interestingly,we found that the cognitive ability was obviously improved,ACh E activity was significantly decreased and neuronal damages were alleviated in cordycepin treated group when compared with the AD model group.Moreover,there was no significant difference of the results between cordycepin treated group and control group.Cordycepin can prevent the cognitive impairments induced by A_β25-35combined with D-galactose,and the potential mechanism could be related to enhancing the function of cholinergic nervous system associated with potentiation of synaptic transmission and reducing the damage of hippocampal neurons.2.The effect of cordycepin on Aβ_25-35-induced LTP impairment.Field excitatory postsynaptic potentials（f EPSPs）recordings were used to study the effect of cordycepin on Aβ_25-35-induced LTP impairment,by using acute isolation of rat hippocampal slices.The results showed that Aβinduced long-term potentiation（LTP）impairment was improved by treatment of cordycepin and this effect is blocked by DPCPX.It demonstrated that cordycepin rescued the impairment of LTP via the A1Rs activation.3.Finally,the effect of cordycepin on synaptic transmission current in rat hippocampal neurons was further studied by patch clamp electrophysiology.spontaneous postsynaptic current（s PSCs）,spontaneous excitatory postsynaptic current（s EPSCs）,spontaneous inhibitory postsynaptic current（s IPSCs）,miniature excitatory postsynaptic currents（m EPSCs）and miniature inhibitory postsynaptic currents（m IPSCs）were recorded by using whole-cell patch clamp techniques.The results showed that the frequency of s PSCs,s EPSCs,s IPSCs,m EPSCs,m IPSCs in CA1 pyramidal neurons were decreased by treatment with cordycepin.Moreover,it also confirmed that the protective effect of cordycepin on neurons depdent on the activation of adenosin A1 receptor.