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Open AccessArticle

Therapeutic Potential of AAV1-Rheb(S16H) Transduction Against Alzheimer’s Disease

1
School of Life Sciences, Kyungpook National University, Daegu 41566, Korea
2
BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea
3
Neural Circuits Research Group, Korea Brain Research Institute, Daegu 41062, Korea
4
Brain Science and Engineering Institute, Kyungpook National University, Daegu 41566, Korea
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Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 41940, Korea
6
Institute of Life Science & Biotechnology, Kyungpook National University, Daegu 41566, Korea
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(12), 2053; https://doi.org/10.3390/jcm8122053
Received: 22 October 2019 / Revised: 14 November 2019 / Accepted: 19 November 2019 / Published: 22 November 2019
(This article belongs to the Section Clinical Neurology)
We recently reported that adeno-associated virus serotype 1-constitutively active Ras homolog enriched in brain [AAV1-Rheb(S16H)] transduction of hippocampal neurons could induce neuron-astroglia interactions in the rat hippocampus in vivo, resulting in neuroprotection. However, it remains uncertain whether AAV1-Rheb(S16H) transduction induces neurotrophic effects and preserves the cognitive memory in an animal model of Alzheimer’s disease (AD) with characteristic phenotypic features, such as β-amyloid (Aβ) accumulation and cognitive impairments. To assess the therapeutic potential of Rheb(S16H) in AD, we have examined the beneficial effects of AAV1-Rheb(S16H) administration in the 5XFAD mouse model. Rheb(S16H) transduction of hippocampal neurons in the 5XFAD mice increased the levels of neurotrophic signaling molecules, including brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), and their corresponding receptors, tropomyosin receptor kinase B (TrkB) and CNTF receptor α subunit (CNTFRα), respectively. In addition, Rheb(S16H) transduction inhibited Aβ production and accumulation in the hippocampus of 5XFAD mice and protected the decline of long-term potentiation (LTP), resulting in the prevention of cognitive impairments, which was demonstrated using novel object recognition testing. These results indicate that Rheb(S16H) transduction of hippocampal neurons may have therapeutic potential in AD by inhibiting Aβ accumulation and preserving LTP associated with cognitive memory. View Full-Text
Keywords: Alzheimer’s disease; Rheb(S16H), neurotrophic signaling; β-amyloid; cognitive impairment Alzheimer’s disease; Rheb(S16H), neurotrophic signaling; β-amyloid; cognitive impairment
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Moon, G.J.; Kim, S.; Jeon, M.-T.; Lee, K.J.; Jang, I.-S.; Nakamura, M.; Kim, S.R. Therapeutic Potential of AAV1-Rheb(S16H) Transduction Against Alzheimer’s Disease. J. Clin. Med. 2019, 8, 2053.

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