Aim In this study, we investigated the effects of a human placenta‐derived drug, Laennec (Japan Bio Products), on memory improvement and neuritic regeneration in Alzheimer's disease model mice, to evaluate the potential of Laennec as a new candidate for anti‐Alzheimer's disease (AD) therapy. Methods The anti‐AD effects of Laennec were evaluated using amyloid β (Aβ)‐treated cortical neurons and the 5XFAD mouse model of AD. Results Laennec significantly improved the dendritic density in normal cortical neurons but not the axon density. Exposure to the peptide fragment Aβ(25–35) for 3 days resulted in significant atrophy in the axons and dendrites of cortical neurons (ddY mice, E14). Laennec significantly improved the density and dendritic length of the Aβ‐treated cortical neurons but did not affect axon atrophy. Synaptic loss induced by Aβ(25–35) was also completely reversed by Laennec treatment. The Laennec‐treated 5XFAD mice (for 15 days, i.p. or p.o.; 5–7 months old, female) showed significant improvement in object recognition memory, but had no reduction in amyloid plaques in the perirhinal cortex, although the reduced dendritic density in the amyloid plaque‐associated sites was significantly increased by Laennec treatment. Furthermore, the components of Laennec were separated based on their molecular weights using ultrafiltration. The Laennec fraction >2 kDa contained the active compounds for dendrite extension. Conclusion Laennec improved object recognition memory and dendritic growth in a model of AD.
We investigated the effects of a heptapeptide, GPPGPAG, on memory improvement and neuritic regeneration in Alzheimer’s disease models to evaluate its potency as a new anti-Alzheimer’s disease (AD) therapy. The anti-AD effects of GPPGPAG were evaluated in Aβ-treated cortical neurons and 5XFAD, a mouse model of AD. Exposure of cortical neurons to Aβ25-35 for 3 days resulted in atrophy of axons and dendrites. Treatment with GPPGPAG improved the dendritic atrophy of Aβ-treated cortical neurons, but not axonal atrophy. Postsynaptic and presynaptic densities under Aβ1-42 exposure were increased by GPPGPAG post treatment. Oral administration of GPPGPAG to 5XFAD mice for 15 days improved significantly object recognition memory and dendritic density. Direct infusion of GPPGPAG into the lateral ventricle of 5XFAD mice for 28 days improved object recognition memory. Following oral administration of GPPGPAG in mice, the undigested heptapeptide was detected in the plasma and cerebral cortex. Analysis of target protein of GPPGPAG in neurons by DARTS method identified 14-3-3ε as a bound protein. The protective effect of GPPGPAG on Aβ1-42-induced dendritic atrophy was canceled by knockdown of 14-3-3ε. Taken together, these results suggest that GPPGPAG is orally available, transfers to the brain, and ameliorates memory dysfunction in AD brain, which is possibly mediated by 14-3-3ε-related dendritic restoration.
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