Pinocembrin improves cognition and protects the neurovascular unit in Alzheimer related deficits.
Amyloid-β (Aβ) peptides accumulate in the brain and initiate a cascade of pathologic events in Alzheimer's disease. The receptor for advanced glycation end products (RAGE) has been implicated to mediate Aβ-induced perturbations in the neurovascular unit (NVU). We demonstrated that pinocembrin exhibits neuroprotection through inhibition of the Aβ and/or RAGE pathway, but the therapeutic role and mechanism involved are not ascertained. Here, we report that a 3-month treatment with pinocembrin prevents the cognition decline in APP/PS1 transgenic mice without altering Aβ burden and oxidative stress. Instead, pinocembrin is effective in conferring neurovascular protection through maintenance of neuropil ultrastructure, reduction of glial activation and levels of inflammatory mediators, preservation of microvascular function, improving the cholinergic system by conserving the ERK-CREB-BDNF pathway, and modulation of RAGE-mediated transduction. Furthermore, in an in vitro model, pinocembrin provides the NVU protection against fibrillar Aβ₁₋₄₂, accompanied by regulation of neurovascular RAGE pathways. Our findings indicate that pinocembrin improves cognition, at least in part, attributable to the NVU protection, and highlights pinocembrin as a potential therapeutic strategy for the prevention and/or treatment of Alzheimer's disease.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
Rui
R
Liu
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
Jin-ze
JZ
Li
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
Jun-ke
JK
Song
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
Dan
D
Zhou
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
Chao
C
Huang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
Xiao-yu
XY
Bai
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
Tao
T
Xie
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
Xue
X
Zhang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
Yong-jie
YJ
Li
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China; School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
Cai-xia
CX
Wu
Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Beijing Geriatric Medical Research Center, Beijing 100053, PR China.
Lan
L
Zhang
Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Beijing Geriatric Medical Research Center, Beijing 100053, PR China.
Lin
L
Li
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China. Electronic address: ttzhang@imm.ac.cn.
Tian-tai
TT
Zhang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China. Electronic address: bessie0420@163.com.
Guan-hua
GH
Du
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D003071:Cognition / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D044950:Flavanones / Q000494:pharmacology* / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D044950:Flavanones; D018696:Neuroprotective Agents; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C016063:pinocembrin
Alzheimer's disease; Amyloid-β peptide; Pinocembrin; The neurovascular unit; The receptor for advanced glycation end products