PMID- 38379185 OWN - NLM STAT- MEDLINE DCOM- 20240222 LR - 20240418 IS - 1755-5949 (Electronic) IS - 1755-5930 (Print) IS - 1755-5930 (Linking) VI - 30 IP - 2 DP - 2024 Feb TI - Targeting blood brain barrier-Remote ischemic conditioning alleviates cognitive impairment in female APP/PS1 rats. PG - e14613 LID - 10.1111/cns.14613 [doi] LID - e14613 AB - AIMS: Alzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies have highlighted the essential role of blood vessels in clearing Abeta, a protein that contributes to AD. Scientists are exploring blood biomarkers as a potential tool for future AD diagnosis. One promising method that may help prevent AD is remote ischemic conditioning (RIC). RIC involves using sub-lethal ischemic-reperfusion cycles on limbs. However, a comprehensive understanding of how RIC can prevent AD and its long-term effectiveness is still lacking. Further research is essential to fully comprehend the potential benefits of RIC in preventing AD. METHODS: Female wild-type (WT) and APP/PS1 transgenic rats, aged 12 months, underwent ovariectomy and were subsequently assigned to WT, APP/PS1, and APP/PS1 + RIC groups. RIC was conducted five times a week for 4 weeks. The rats' depressive and cognitive behaviors were evaluated using force swimming, open-field tests, novel objective recognition, elevated plus maze, and Barnes maze tests. Evaluation of the neurovascular unit (NVU), synapses, vasculature, astrocytes, and microglia was conducted using immunofluorescence staining (IF), Western blot (WB), and transmission electron microscopy (TEM). Additionally, the cerebro-vasculature was examined using micro-CT, and cerebral blood flow (CBF) was measured using Speckle Doppler. Blood-brain barrier (BBB) permeability was determined by measuring the Evans blue leakage. Finally, Abeta levels in the rat frontal cortex were measured using WB, ELISA, or IF staining. RESULTS: RIC enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in APP/PS1 transgenic rats. Additionally, the intervention protected NVU in the rat frontal cortex, as evidenced by (1) increased expression of TJ (tight junction) proteins, pericyte marker PDGFRbeta, and glucose transporter 1 (GLUT1), as well as decreased VCAM1; (2) mitigation of ultrastructure impairment in neuron, cerebral vascular, and astrocyte; (3) upregulation of A2 astrocyte phenotype markers and downregulation of A1 phenotype markers, indicating a shift toward a healthier phenotype. Correspondingly, RIC intervention alleviated neuroinflammation, as evidenced by the decreased Iba1 level, a microglia marker. Meanwhile, RIC intervention elevated CBF in frontal cortex of the rats. Notably, RIC intervention effectively suppressed Abeta toxicity, as demonstrated by the enhancement of alpha-secretase and attenuation of beta-secretase (BACE1) and gamma- secretase and Abeta1-42 and Abeta1-40 levels as well. CONCLUSION: Chronic RIC intervention exerts vascular and neuroprotective roles, suggesting that RIC could be a promising therapeutic strategy targeting the BBB and NVU during AD development. CI - (c) 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd. FAU - Ma, Yuxuan AU - Ma Y AD - International Science & Technology Cooperation Base of Geriatric, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China. FAU - Sun, Wuxiang AU - Sun W AD - School of Basic Medical Science, North China University of Science and Technology, Tangshan, Hebei, China. FAU - Bai, Jing AU - Bai J AD - School of Basic Medical Science, North China University of Science and Technology, Tangshan, Hebei, China. FAU - Gao, Fujia AU - Gao F AD - International Science & Technology Cooperation Base of Geriatric, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China. FAU - Ma, Haoran AU - Ma H AD - International Science & Technology Cooperation Base of Geriatric, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China. FAU - Liu, Huiyu AU - Liu H AD - International Science & Technology Cooperation Base of Geriatric, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China. FAU - Hu, Jiewei AU - Hu J AD - School of Basic Medical Science, North China University of Science and Technology, Tangshan, Hebei, China. FAU - Xu, Chao AU - Xu C AD - International Science & Technology Cooperation Base of Geriatric, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China. FAU - Zhang, Xin AU - Zhang X AD - International Science & Technology Cooperation Base of Geriatric, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China. FAU - Liu, Zixuan AU - Liu Z AD - School of Basic Medical Science, North China University of Science and Technology, Tangshan, Hebei, China. FAU - Yuan, Tao AU - Yuan T AD - International Science & Technology Cooperation Base of Geriatric, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China. FAU - Sun, Chenxu AU - Sun C AD - School of Basic Medical Science, North China University of Science and Technology, Tangshan, Hebei, China. FAU - Huang, Yuanyuan AU - Huang Y AD - School of Basic Medical Science, North China University of Science and Technology, Tangshan, Hebei, China. FAU - Wang, Ruimin AU - Wang R AUID- ORCID: 0000-0002-1842-6291 AD - International Science & Technology Cooperation Base of Geriatric, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China. AD - School of Basic Medical Science, North China University of Science and Technology, Tangshan, Hebei, China. LA - eng GR - 81671223/National Natural Science Foundation of China/ GR - ZD2021087/Science and Technology Project of Hebei Education Departmen/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - CNS Neurosci Ther JT - CNS neuroscience & therapeutics JID - 101473265 RN - 0 (Amyloid beta-Peptides) RN - 0 (Amyloid beta-Protein Precursor) RN - EC 3.4.- (Amyloid Precursor Protein Secretases) RN - EC 3.4.23.- (Aspartic Acid Endopeptidases) RN - 0 (Presenilin-1) SB - IM MH - Mice MH - Rats MH - Female MH - Animals MH - Blood-Brain Barrier/metabolism MH - Amyloid beta-Peptides/metabolism MH - Amyloid beta-Protein Precursor/genetics/metabolism MH - Amyloid Precursor Protein Secretases/genetics MH - Mice, Transgenic MH - Rats, Transgenic MH - Aspartic Acid Endopeptidases/genetics/metabolism/therapeutic use MH - *Alzheimer Disease/drug therapy MH - *Cognitive Dysfunction/diagnostic imaging/therapy MH - Disease Models, Animal MH - Presenilin-1/genetics/metabolism PMC - PMC10879645 OTO - NOTNLM OT - Alzheimer's disease OT - blood-brain barrier OT - cognitive impairment OT - neuron vascular unit OT - remote ischemic conditioning COIS- The authors have declared that no competing interest exists. EDAT- 2024/02/21 11:15 MHDA- 2024/02/22 12:11 PMCR- 2024/02/20 CRDT- 2024/02/21 00:24 PHST- 2023/11/16 00:00 [revised] PHST- 2023/06/16 00:00 [received] PHST- 2023/11/26 00:00 [accepted] PHST- 2024/02/22 12:11 [medline] PHST- 2024/02/21 11:15 [pubmed] PHST- 2024/02/21 00:24 [entrez] PHST- 2024/02/20 00:00 [pmc-release] AID - CNS14613 [pii] AID - 10.1111/cns.14613 [doi] PST - ppublish SO - CNS Neurosci Ther. 2024 Feb;30(2):e14613. doi: 10.1111/cns.14613.