The n-terminal 5-MER peptide analogue P165 of amyloid precursor protein exerts protective effects on SH-SY5Y cells and rat hippocampus neuronal synapses

The disturbance of the insulin-signaling pathway plays an important role in Alzheimer's disease. Resistance to insulin signaling renders neurons energy-deficient and vulnerable to oxidization or other metabolic insults and impairs synaptic plasticity. In search of neuroprotective drugs, we synthesized a peptide analogue, P165, an active domain of the soluble amyloid precursor protein, which is resistant to degradation and is suitable for oral administration in a clinical setting. Initially, we confirmed that P165 can protect cells from streptozotocin-caused damage and stimulate cell outgrowth using cultured SH-SY5Y cell lines treated with streptozotocin. P165 significantly reduced lactate dehydrogenase leakage from damaged cells, thereby rescuing cell energy production. Insulin signaling such as insulin receptor substrate-1 (IRS-1) and phosphoinositide 3-kinase (PI3K) proteins were upregulated to stimulate cell survival and growth. We proceeded to investigate the effect of P165 on streptozotocin-treated Alzheimer's disease (AD) rats. The data showed that P165 protected synaptic loss and dysfunction by increasing synaptophysin and PSD-95 (post synaptic density-95), while simultaneously decreasing α-synuclein expression. Moreover, animal behavior testing clearly showed that P165 increased rats' learning and memory activity. Overall, these results constitute evidence that peptide analogue 165 may protect synapse and improve learning and memory ability in AD.

Research Highlights▶P165 protects cells from streptozotocin-caused damage and stimulate cell outgrowth. ▶P165 reduces lactate dehydrogenase leakage, thereby rescuing cell energy production. ▶P165 protects synapses by increasing synaptophysin, PSD and decreasing α-synuclein. ▶P165 improves learning and memory ability in AD.