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Neuropharmacology. 2018 Jan;128:282-292. doi: 10.1016/j.neuropharm.2017.10.028. Epub 2017 Oct 25.

Direct pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity.

Author information

1
School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol, UK.
2
Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea.
3
Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Republic of Korea.
4
Department of Aquatic Biomedical Sciences, School of Marine Biomedical Science, College of Ocean Science, Jeju National University, Jeju, Republic of Korea.
5
Department of Herbal Medicinal Pharmacology, College of Herbal Bio-industry, Daegu Haany University, Kyungsan, Republic of Korea.
6
School of Natural Resources and Environmental Science, Kangwon National University, ChoonCheon, Republic of Korea.
7
Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan, Republic of Korea.
8
Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 1 Hoeki-dong, Dongdaemoon-Gu, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 1 Hoeki-dong, Dongdaemoon-Gu, Seoul, Republic of Korea. Electronic address: jhryu63@khu.ac.kr.
9
Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan, Republic of Korea. Electronic address: mose79@dau.ac.kr.

Abstract

Amyloid β (Aβ) is a key mediator for synaptic dysfunction and cognitive impairment implicated in Alzheimer's disease (AD). However, the precise mechanism of the toxic effect of Aβ is still not completely understood. Moreover, there is currently no treatment for AD. Protein kinase B (PKB, also termed Akt) is known to be aberrantly regulated in the AD brain. However, its potential function as a therapeutic target for AD-associated memory impairment has not been studied. Here, we examined the role of a direct Akt activator, SC79, in hippocampus-dependent memory impairments using Aβ-injected as well as 5XFAD AD model mice. Oligomeric Aβ injections into the 3rd ventricle caused concentration-dependent and time-dependent impairments in learning/memory and synaptic plasticity. Moreover, Aβ aberrantly regulated caspase-3, GSK-3β, and Akt signaling, which interact with each other in the hippocampus. Caspase-3 and GSK-3β inhibitor ameliorated memory impairments and synaptic deficits in Aβ-injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both Aβ-treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD.

KEYWORDS:

Akt; Alzheimer's disease; Amyloid β; Long-term potentiation; Memory

[Indexed for MEDLINE]

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