Metal ion-induced aggregation of A beta into insoluble plaques is a centralfactor in Alzheimer's disease.Zn^(2+) is the only physiologically available transition metal ionresponsible for aggregating A beta at pH 7.4.To make it clear that the neurotoxicity ofZn^(2+)-induced aggregation of A beta on neurons is the key to understand A beta mechanism of actionfurther.In this paper,we choose A/?(10-21) as the model fragment to research hippocampal CA1pyramidal neurons.For the first time,we adopt the combination of spectral analysis with patch-clamptechnique for the preliminary study of the mutual relations of Zn^(2+),A beta and ion channel fromthe cell level.The following expounds upon the effects and mode of action of two forms (unaggregatedand aggregated) of A beta(10-21) on hippocampus outward potassium channel three processes(activation,inactivation and reactivation).It also shows the molecular mechanics of AD from thechannel level.These results are significant for the further study of A beta nosogenesis and thedevelopment of new types of target drugs for the treatment of AD.
The biochemical effects of gadolinium chloride were studied using high-resolution IH nuclear magnetic resonance （NMR） spec- troscopy to investigate the biochemical composition of tissue （liver and kidney） aqueous extracts obtained from control and gadolinium chloride （GdCl3） （10 and 50 mg/kg body weight, intraperitoneal injection, i.p.） treated rats. Tissue samples were collected at 48, 96 and 168 h p.d. after exposure to GdCI3, and extracted using methanol/chloroform solvent system. ^1H NMR spectra of tissue extracts were analyzed by pat- tern recognition using principal components analysis. The liver damages caused by GdCl3 were characterized by increased succinate and decreased glycogen level and elevated lactate, alanine and betaine concentration in liver. Furthermore, the increase of creatine and lactate, and decrease of glutamate, alanine, phosphocholine, glycophosphocholine （GPC）, betaine, myo-inositol and trimethylamine N-oxide （TMAO） levels in kidney illustrated kidney disturbance induced by GdCl3.
3-benzidino-5-methyl-6-phenylpyridazine (BMP) inhibited electric eel acetylcholinesterase (AChE), with IC50 being 0.58 μmol·L-1. As an AChE inhibitor, the effects of BMP on delayed rectifier potassium current (IK(DR)) and transient outward potassium current (IK(A)) in acutely isolated rat hippocampal pyramidal neurons were studied using the whole cell patch-clamp technique. BMP (0.1―50 μmol·L-1) inhibited IK(DR) and IK(A) in a concentration-dependent and voltage-independent manner. The IC50 value for the blocking action of BMP on IK(DR) and IK(A) was calculated to be 2.92 and 2.11 μmol·L-1, respectively. At the concentration of 10 μmol·L-1, BMP shifted the activation curve of IK(DR) to negative potential by 8.85 mV. Meanwhile, at the concentration of 10 μmol·L-1, BMP also shifted the activation and the steady-state inactivation curve of IK(A) to negative potential by 5.82 mV and 10.02 mV, respectively. In conclusion, BMP potently inhibits IK(DR) and IK(A) in rat hippocampal pyramidal neurons, which may contribute to restore the damaged central nervous system.
Although humans have spent exactly 100 years combating Alzheimer’s disease (AD), the molecular mechanisms of AD remain unclear. Owing to the rapid growth of the oldest age groups of the popula-tion and the continuous increase of the incidence of AD, it has become one of the crucial problems to modern sciences. It would be impossible to prevent or reverse AD at the root without elucidating its molecular mechanisms. From the point of view of metal-amyloid-β peptide (Aβ) interactions, we review the molecular mechanisms of AD, mainly including Cu2+ and Zn2+ inducing the aggregation of Aβ, cata-lysing the production of active oxygen species from Aβ, as well as interacting with the ion-channel-like structures of Aβ. Moreover, the development of therapeutic drugs on the basis of metal-Aβ interactions is also briefly introduced. With the increasingly rapid progress of the molecular mechanisms of AD, we are now entering a new dawn that promises the delivery of revolutionary developments for the control of dementias.
JIAO Yong & YANG Pin Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan 030006, China
