| Although it is generally accepted that amyloid P protein (ApP) contributes to the pathogenesis of Alzheimer's disease, the precise role of APP in the development of memory loss and cognitive deficits of Alzheimer's disease has not been fully understood. It is reported that ApP could impaire learning and memory by affecting long term potentiation (LTP) in hippocampus. According to our previous experiments, AP31-35, a shorter fragment of ApP, could also suppress the LTP evoked in hippocampal slices in vitro. In order to determine the effects of APP on hippocampal LTP in vivo and to analyze it's possible mechanisms, the present study examined the effects of two synthetic APP fragments, A P31-35 and APP25-35, on the basic synaptic transmission, the high frequency stimuli (HFS)-. induced LTP, and the paired pulse- induced facilitation. Stimulating electrodes were inserted into the Schaffer's collaterals and extracellular recording electrode was inserted into the stratum radiatum of the hippocampal CA1 region for recording the fieldpotential of EPSPs evoked by single electrical stimuli given consecutively with an interval of 30 sec. A P31-35 and A P25-35 were injected into the lateral ventricle on the same side.The results showed that: (1) by applying HFS, the amplitudes of EPSPs increased to 173.4 + 6.9% just after HFS, as compared to that measured before HFS and set arbitrarily as 100%, with the largest increase of 190.8 + 7.9% at about 15 min following HFS, and being still 184.5 + 8.8% at 60 min (n=14); (2) after injection of 25 nmol or 50 nmol A P31-35 or AJ3P25-35, there existed no effect on the basic EPSPs evoked by single electrical stimuli during a period even lasting for 1 h; (3) 5 min after injection of 50 nmol A P31-35, the HFS-induced LTP of EPSPs, as measured 1 h later, were significantly suppressed, showing as 126.7 5.1% (n=6) as compared to 184.5 8.8% (n=14 ,P<0.05) induced in control group using the same protocol, while the injection of APP25-35 at the same molar concentration also exhibited a similar suppression on LTP (125.5 109%, n=7), being no difference with that measured following APP31-35 injection; (4) the suppressivc effects of APP31-35 on LTP showed a dose-dependent manner as follows: when HFS was given 5 min after injection of 50 nmol A P31-35 and LTP was measured at 5 min, 45 min and 60 min post HFS, respectively, the resulting LTP values were 139.5 12.4 %, 135.8 5.3%, and 126.7 5.1%, while when 25 nmol A P31-35 wasgiven and LTP was measured by the same protocol, the LTP values were 148.7 5.7%, 143.0 6.3%, and 142.0 5.5%, respectively, indicating that this higher dosage of AP31-35 exhibited a more extensive suppression on LTP at every time-points than that of lower dosage; and more evidently, when HFS was given 1 h after 25 nmol A P31-35 injection and LTP was measured 30 min after HFS, a more extensive suppression of LTP (126.2 3.7%, n=5) could be observed than that of 143.5 7.9% (n=6, P<0.05) observed when HFS was given 5 min only after AP3 1-35 injection and LTP was measured at the same time-point; (5) application of 25 nmol or 50 nmol APP3 1-35 or APP25-35 showed no significant effect on paired pulse-evoked facilitation; and (6) the pretreatment of verapamil (2.5mg/kg i.p.), a kind of L-type Ca2+ channels blocker, did not change the suppressive effect of APP31-35 on LTP (129.5 11.3 %,n=4), as compared to that in control group (126.7 5.1 %, n=6, P>0.05).The results suggest that: (1) APP may contribute to loss of memory and cognitive functions in vivo, (2) APP31-35 may be the shorter fragment that is responsible for exhibiting the suppressive action on LTP in full-length APR (3) APP3 1-35 or APP25-35 may suppress LTP by way(s) that is independent to the weakening of presynaptic neurotransmitter release; (4) the ApP31-35 induced suppression of LTP may not rely, if any, on the activation of L-type voltage-dependent Ca2+ channels. |
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