Effects Of S14G-humanin On Long-term Potentiation Inhibition Induced By β-amyloid Protein In Mouse Hippocampal CA1 Region

Backgroud and objective:Alzheimer's disease (AD), the most common clinical type of dementia in elderly population, is an insidious onset, neurodegenerative disease in center nervous system, characterized by irreversible, progressive loss of memory, cognitive impairment, speech disorders and personality change. Despite pathogenesis of AD is not yet completely clear, it's generally agreed thatβ-amyloid protein (Aβ) aggregation, fibrosis, deposition, formation and toxic effects of Aβplaque is an important pathological basis of development of AD. Growing studies have shown that synaptic dysfunction, which caused by soluble Aβ, is the key pathological process in early stage of AD, and closely related to mild cognitive impairment in preclinical stage of AD. Humanin(HN)is a polypeptide discovered in occipital lobes of AD patients. We and others studies indicated that HN and its derivative (HNG) can antagonize the neurotoxicity of soluble Aβand reduce cognitive impairment of the AD transgenic animal model. That means HN and its derivative could be expected to be a new medicine for AD treatment. But the neuroprotective mechanism of HN still remains unclear so far. This study investigate the effect of HNG on the impairment of synaptic plasticity induced by soluble Aβin hippocampal CA1 region at the level of synaptic network with planar multi-electrode arrays (MEA) for the first time. The result will provide experimental evidence and theoretical foundation to study the neuroprotective mechanism of HNG in depth.Methods:Investigate the effect of soluble Aβ, HNG and soluble Aβincubated with different concentrations (100nmol/L, 200nmol/L, 400nmol/L) of HNG on the electrophysiological properties of basic synaptic transmission at the level of synaptic network and the effect of HNG on the impairment of synaptic plasticity induced by soluble Aβin hippocampal CA1 region at the level of synaptic network by using mutli-channel extra-cellular recording system (MED64 system) in hippocampal CA1 region in vitro.Results:1,Stimulated with same intensity, the propagation of PrV and fEPSP in hippocampal CA1 region in each treatment group (Aβ25-35 400 nmol/L group,HNG 400 nmol/L group,Aβ25-35 400 nmol/L + HNG 100 nmol/L group,Aβ25-35 400 nmol/L+HNG 200 nmol/L group and Aβ25-35 400 nmol/L + HNG 400 nmol/L group) showed no significant difference compared with the normal control group(P>0.05);2,Compared with the normal control group, the propagation of LTP in hippocampal CA1 region which recorded at 60 min after induced byθfrequency was significantly reduced by Aβ25-35 (P<0.05); the propagation of LTP in HNG group showed no significant difference (P>0.05);3,Compared with normal controls, the propagation of LTP in hippocampal CA1 region was significantly reduced in Aβ25-35 400nmol/L+HNG 100 nmol/L group (P<0.05). There was not statistically significant difference between the Aβ25-35+HNG 100nmol/L group and the Aβ25-35 group(P>0.05). The propagation of LTP in Aβ25-35 400nmol/L +HNG 200nmol/L group and Aβ25-35 400nmol/L +HNG 400nmol/L group both significantly increased compared with Aβ25-35 group (P<0.05). The Aβ25-35 400nmol/L +HNG 400nmol/L group and HNG 400nmol/L group all showed no significant difference compared with control group(P>0.05).Conclusions:1,Soluble Aβ, HNG and soluble Aβincubated with different concentrations (100nmol/L, 200nmol/L, 400nmol/L)of HNG showed no effect on the electrophysiological properties of basic synaptic transmission at the level of synaptic network in hippocampal CA1 region in vitro;2,Low concentration of soluble Aβmay impair synaptic plasticity by inhibiting the propagation of LTP at the level of synaptic network in hippocampal CA1 region;3,HNG can prevent and reverse soluble Aβ-induced LTP impairment in hippocampal CA1 region at the level of synaptic network, suggesting that HNG might protect synaptic plasticity from Aβtoxicity.