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.
Key Laboratory of Chinese Internal Medicine (Beijing University of Chinese Medicine), Ministry of Education, Beijing 100700, People's Republic of China.
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Wang
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Jiang
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Cui
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Yue
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Su
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Sun
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Sheng
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Tian
D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000627:therapeutic use; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000008:administration & dosage / Q000633:toxicity; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D016708:Synaptophysin / Q000096:biosynthesis; D051844:alpha-Synuclein / Q000096:biosynthesis
C000602555:APP5-mer peptide; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000964:Antimetabolites, Antineoplastic; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D016708:Synaptophysin; D051844:alpha-Synuclein; D013311:Streptozocin