PMID- 31881998 OWN - NLM STAT- MEDLINE DCOM- 20200806 LR - 20200806 IS - 1758-9193 (Electronic) VI - 11 IP - 1 DP - 2019 Dec 27 TI - Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model. PG - 110 LID - 10.1186/s13195-019-0569-x [doi] LID - 110 AB - BACKGROUND: The persistence of adult hippocampal neurogenesis (AHN) is sharply decreased in Alzheimer's disease (AD). The neuropathologies of AD include the presence of amyloid-beta deposition in plaques, tau hyperphosphorylation in neurofibrillary tangles, and cholinergic system degeneration. The focused ultrasound (FUS)-mediated blood-brain barrier opening modulates tau hyperphosphorylation, the accumulation of amyloid-beta proteins, and increases in AHN. However, it remains unclear whether FUS can modulate AHN in cholinergic-deficient conditions. In this study, we investigated the effect of FUS on AHN in a cholinergic degeneration rat model of dementia. METHODS: Adult male Sprague-Dawley rats (n = 48; 200-250 g) were divided into control (phosphate-buffered saline injection), 192 IgG-saporin (SAP), and SAP+FUS groups; in the two latter groups, SAP was injected bilaterally into the lateral ventricle. We applied FUS to the bilateral hippocampus with microbubbles. Immunohistochemistry, enzyme-linked immunosorbent assay, immunoblotting, 5-bromo-2'-deoxyuridine labeling, an acetylcholinesterase assay, and the Morris water maze test were performed to assess choline acetyltransferase, acetylcholinesterase activity, brain-derived neurotrophic factor expression, neural proliferation, and spatial memory, respectively. Statistical significance of differences in between groups was calculated using one-way and two-way analyses of variance followed by Tukey's multiple comparison test to determine the individual and interactive effects of FUS on immunochemistry and behavioral analysis. P < 0.05 was considered significant. RESULTS: Cholinergic degeneration in rats significantly decreased the number of choline acetyltransferase neurons (P < 0.05) in the basal forebrain, as well as AHN and spatial memory function. Rats that underwent FUS-mediated brain-blood barrier opening exhibited significant increases in brain-derived neurotrophic factor (BDNF; P < 0.05), early growth response protein 1 (EGR1) (P < 0.01), AHN (P < 0.01), and acetylcholinesterase activity in the frontal cortex (P < 0.05) and hippocampus (P < 0.01) and crossing over (P < 0.01) the platform in the Morris water maze relative to the SAP group after sonication. CONCLUSIONS: FUS treatment increased AHN and improved spatial memory. This improvement was mediated by increased hippocampal BDNF and EGR1. FUS treatment may also restore AHN and protect against neurodegeneration, providing a potentially powerful therapeutic strategy for AD. FAU - Shin, Jaewoo AU - Shin J AD - Department of Neurosurgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. AD - Brain Korea 21 PLUS Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. FAU - Kong, Chanho AU - Kong C AD - Department of Neurosurgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. FAU - Lee, Jihyeon AU - Lee J AD - Department of Neurosurgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. AD - Brain Korea 21 PLUS Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. FAU - Choi, Bo Young AU - Choi BY AD - Department of Physiology, Hallym University College of Medicine, Chuncheon, 24252, Republic of Korea. FAU - Sim, Jiyeon AU - Sim J AD - Department of Neurosurgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. AD - Brain Korea 21 PLUS Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. FAU - Koh, Chin Su AU - Koh CS AD - Department of Neurosurgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. FAU - Park, Minkyung AU - Park M AD - Department of Neurosurgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. AD - Brain Korea 21 PLUS Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. FAU - Na, Young Cheol AU - Na YC AD - Department of Neurosurgery, Catholic Kwandong University College of Medicine, International St Mary's Hospital, Incheon Metropolitan City, 22771, Republic of Korea. FAU - Suh, Sang Won AU - Suh SW AD - Department of Physiology, Hallym University College of Medicine, Chuncheon, 24252, Republic of Korea. FAU - Chang, Won Seok AU - Chang WS AD - Department of Neurosurgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. changws0716@yuhs.ac. FAU - Chang, Jin Woo AU - Chang JW AUID- ORCID: 0000-0002-2717-0101 AD - Department of Neurosurgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. jchang@yuhs.ac. AD - Brain Korea 21 PLUS Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. jchang@yuhs.ac. LA - eng GR - 2016M3C7A1914123/National Research Foundation of Korea/International GR - HI19C0060/Korea Health Industry Development Institute/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191227 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 0 (Brain-Derived Neurotrophic Factor) RN - EC 2.3.1.6 (Choline O-Acetyltransferase) RN - EC 3.1.1.7 (Acetylcholinesterase) SB - IM MH - Acetylcholinesterase/metabolism MH - Animals MH - Blood-Brain Barrier/metabolism/pathology/physiopathology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cell Proliferation/physiology MH - Choline O-Acetyltransferase/metabolism MH - Cholinergic Neurons/metabolism/*pathology MH - Cognition/*physiology MH - Dementia/metabolism/pathology/*physiopathology MH - Hippocampus/metabolism/pathology/*physiopathology MH - Male MH - Maze Learning/*physiology MH - Neurogenesis/*physiology MH - Rats MH - Rats, Sprague-Dawley MH - Spatial Memory/physiology MH - *Ultrasonography PMC - PMC6933667 OTO - NOTNLM OT - Alzheimer's disease OT - Brain-derived neurotrophic factor OT - Dementia OT - Hippocampus OT - Microbubbles OT - Neuropathology OT - Rats, Sprague-Dawley OT - Sonication COIS- The authors declare that they have no competing interests. EDAT- 2019/12/29 06:00 MHDA- 2020/08/07 06:00 PMCR- 2019/12/27 CRDT- 2019/12/29 06:00 PHST- 2019/07/10 00:00 [received] PHST- 2019/12/12 00:00 [accepted] PHST- 2019/12/29 06:00 [entrez] PHST- 2019/12/29 06:00 [pubmed] PHST- 2020/08/07 06:00 [medline] PHST- 2019/12/27 00:00 [pmc-release] AID - 10.1186/s13195-019-0569-x [pii] AID - 569 [pii] AID - 10.1186/s13195-019-0569-x [doi] PST - epublish SO - Alzheimers Res Ther. 2019 Dec 27;11(1):110. doi: 10.1186/s13195-019-0569-x.