Neuron-synapse loss and dementias

Abstract

Abstract: Basic and clinical study of Alzheimer’s disease showed that senile plagues and neurofibrillary tangle are not related to the degree of cognitive impairment. Synaptic loss occur in Alzheimer’s disease and other neurodegenerative dementias which block LTP，induce neuropsychological dysfunction and memory deficit . Neuron-synapses or synaptic loss was considered as main cause of dementias. Several hidden toxins such as oligomer of Aβ and phosphorylated Tau,glutamate receptor at extrasynaptic region and shank protein can lead to synaptic loss. Therefore，strategy for AD treatment is that ① To clean oligomer by native oligomer of Aβ immunotherapy. ②To maintain the normal homeostasis of synaptic protein by mTOR(a protein kinase) and UPS. ③To activate synaptic NMDA receptors or block extrasynaptic NMDA receptors. ④To increase hippocampal neurogenesis and synaptogenesis. In our recent study，ginsenoside Rg1 and Ppt were proved to increase synaptic plasticity in both efficacy and structure as well as increase neurogenesis both in vitro and in vivo，under physiological and pathological circumstances，indicating that they are promising agents for preventing and treatment of dementias and many kinds of memory impairment.

Key words: neuron-synapse loss, dementias, cognition, long-term , potentiation(LTP), NMDA receptor, gensenoside Rg1 and Ppt, neurogenesis, synaptogenesis

ZHANG Juntian. Neuron-synapse loss and dementias[J]. Acta Neuropharmacologica, 2011, 1(1): 1-15.

References

1   Holtzman DM. Alzheimer’s disease: Moving towards a vaccine. Nature news，2008，454(Jul,24):418-420
2   Holmes C，Boche D，Wilkinson D，et al.Long-term effects of Aβ42 immunisation in Alzheimer’s disease，placebo-controlled phase l trial [J]. Lancet. 2008，372(9634):216-223: follow-up of a randomized
3   Wilcock DM，Gharkholonarehe N，William E. Van Nostrand，et al. Amyloid reduction by amyloid-β vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer’s disease[J]. J Neurosci. 2009，29(25):7957-7965
4   A. J. Bayer，R. Bullock，R. W. Jones，D. Wilkinson，et al. Evaluation of the safety and immunogenicity of synthetic Aβ42 in patient with AD[J]. Neurology. 2005，64(1):94-101
5   徐庆中，卢德宏，董彬，等. Alzheimer’型老年痴呆的神经病理学[M].//盛树力. 老年性痴呆从分子生物学到临床诊治. 北京：科学文献出版社，1998:78-79
6   Selkoe O J. Alzheimer’s disease in a synaptic failure[J]. Science，2000，298(5594):789-791
7   Terry RD. Some morphometric aspects of the brain in senile dementia of the Alzheimer type[J]. Ann Neurol. 1981，10(2):184-192
8   Ball MJ.Neuronal loss ，neurofibrillary tangle and granulo vascular degeneration in the hippocampus with aging brain and senile dementia，A quantitative study[J]. Acta Neuropathol. 1977，37(2):111-118
9   Marijke A. M. Lemmens，Annerieke S. R. Sierksma，Bart P. F. Rutten，et al. Age-related changes of neuron numbers in the frontal cortex of a transgenic mouse model of Alzheimer’s disease[DB/OL]. Brain Struct Funct，2011，DOI:10.1007/s00429-011-0305-1 http://www.springerlink.com/content/f6182760623073g6/
10 Pittman RN. Asynchronous death as a characteristic feature of apoptosis.Cell death and disease of the neurous system[M]// Koliatsos，VE eds. Totowa，Humane Press，1999:29-48
11 Carl W.Cotman，Haoyu Qian，Aileen J. Anderson. Cellular signaling pathways in neuronal apoptosis[M]//Marten E.A.Reith. Cerebral signal transduction. Humana press，2000:175- 206
12 Alvarez VA and Sabatini BL.Anatomical and physiological plasticity of dendritic spines[J]. Annu Rev Neurosci. 2007，30:79-97
13 Claudia Ferez-Cruz. Reduced spine density in specific regions of CA1 pyramidal neurons in two transgenic mouse models of Alzheimer’s disease[J]. J Neurosci. 2011，31(10):3926-3934
14 Ryan Clare，Victoria G. King，Martin Wirenfeldt，Harry V. Vinters.Synapse loss in dementias[J]. J Neurosci Res. 2010，88(10):2083-2090
15 Alvarez VA，Sabatini BL，Annu. Rev. Anatomical and physiological plasticity of dendritic spines[J]. Annu Rev Neurosci. 2007，30:79-97
16 Mattson MP. Pathways towards and away from Alzheimer’s disease[J]. Nature. 2004，430(7000):631-639
17 Ming Jin，Nina Shepardson，Ting Yang，et al. Soluble amyloid β-protein dimmers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration[J]. Proc Natl Acad Sci U S A. 2011，108(14):5819-5824.
18 Giles E，Hardinham, Hilmar Bading. Synaptic versus extrasynaptic NMDA receptor signaling:implications for neurodegenerative disorders[J]，11(10):682-696. Nat Rev Neurosci. 2010
19 张均田，郑永芳.细胞内钙和钙通道[M]//韩济生.神经科学原理.上册2版，北京:北京医科大学出版社，1999:222-240
20 Anthony Lau，Michiael Tymianski. Glutamate receptors，Neurotoxicity and neurodegeneration[J]. Eur J Physiol,2010,460(2):525-542.
21 Kelly A. Foster，Nathan McLaughlin，Dieter Edbauer，et al. Distinct roles of NR2A and NR2B cytoplasmic tails in long term potentiation[J]. The journal of neuroscience，2010，30(7):2676-2685
22 Boeckers TM. The postsynaptic density[J]. Cell Tissue Res. 2006，326(2):409-422
23 Selkoe DJ.Defining molecular targets to prevent Alzheimer’s disease[J]. Arch Neurol. 2005，62(2):192-195
24 Giles E. Hardingham，Hilmar Bading. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders[J]. Nat Rev Neurosci. 2010，11(10):682-696
25 Gong YS. Lippa CF. Disruption of the postsynaptic density in Alzheimer’s disease and other neurodegenerative dementias[J]. Am J Alzheimers Dis Other Demen. 2010，25(7):547-555
26 Sylvain Lesne，Ming Teng Koh，Linda Kotilinek，et al. A specific amyloid-β protein assembly in the brain impairs memory[J]. Nature. 2006，440(7082):352-357
27 Yuesong Gong，Lei Chang，Kirsten L. Viola，et al.Alzheimer's disease-affected brain: Presence of oligomeric A(beta) ligands (ADDLs) suggests a molecular basis for reversible memory loss [J]. Proc Natl Acad Sci U S A. 2003，100(18):10417-10422
28 Mary P. Lambert，Pauline T. Velasco，Lei Chang，et al. Monoclonal antibodies that target pathological assemblies of Aβ [J] . J Neurochem. 2007，100(1):23-35
29 Pascale N. Lacor，Maria C. Buniel，Lei Chang，et al.Synaptic Targeting by Alzheimer’s-Related Amyloid β Oligomers[J]. J Neurosci. 2004，24(45):10191-10200
30 Fernanda G. De Felicea，Marcelo N. N. Vieirab，Theresa R. Bomfimb，et al. Protection of synapses against Alzheimer’s-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers[J]. Proc Natl Acad Sci U S A. 2009，106(6):1971-1976
31 Ehud Cohen，Jan Bieschke，Rhonda M. Perciavalle，et al. Opposing activities protect against age-Onset proteotoxicity[J] . Science. 2006，313(5793):1604-1610
32 Wtanabe H. Effect of ginseng on spontaneous motor activity ，water maze and dopaminergic in old rats[M]//Shibatas. Recent advances in ginseng studies. Tokyo: Hirokawa Publishing company，1989:73-81
33 Petkov V. Ginseng as a remedy regulating aging processes in brain (Experiment of rats)[M]//Shibata S .Recent advances in ginging studies[M]. Tokyo: Hirokawa Publishing company，1989:83-98
34 Saito H.Effects of ginsenside Rb1 and Rg1 on learning and memory[M]//Shibata S. Recent Advances in Ginseng studies. Tokyo: Hirokawa Publishing company，1989:99-111.
35 Saito H，Tsuchiya M，Naba S，et al. Effects of panax ginseng root on conditioned avoidance respense in rats[J]. Jpn J Pharmacol. 1977，27(4):509-516
36 Kennedy D.The effect of ginseng on memory and mood，2002.[M]. Korean society of Ginseng Advances in ginsong research
37 Lawrence C H Wang，Lee T. Effects of ginseng saponins in energy metabolism，memory and anti-neurotoxicity[M]. Korean Society of Ginseng Advances in ginseng research. 2002:27-46
38 Doyle CA, Slater P. Localization of neuronal and endothelial nitric oxide synthase isoforms in human hippocampus[J]. Neuroscience. 1997，76(2):387-395
39 Wang X Y，Zhang J T. NO mediates ginsenoside Rg1 and Rb1-induced long-term potentiation in anesthetized rats[J]. Acta Pharmacol Sin. 2001，22(12):1099-1102
40 Jianfei Xue，Zhijun Liu，Jinfeng Hu，et al. Ginsenoside Rg1 promotes neurotransmitter release by modulating phosphorylation of synapsins through a cAMP-dependent protein kinase pathway[J]. Brain Res. 2006，1106(1):91-98
41 杨迎，张均田，石成璋，等. 人参皂甙Rb1和Rg1促智作用机制的探讨──对小鼠脑神经发育的影响[J]. 药学学报.，29(4):241-245 1994
42 Higashi H and Chen N. Ganglioside/protein kinase signals triggering cytoskeletal actin reorganization[J]. Glycoconj J. 2004，20(1):49-58
43 J.Woodland Hastings and James G. Morin. Photons for reporting molecular events:green fluorescent protein and four luciferase systems[M]//Martin Chalfie and Steven R.Kain. Green fluorescent protein:properties application and protocols. New York: Wiley-liss, 1998:3-15
44 陈乃宏.图像可视化技术在神经药理学研究中的应用[M]//张均田，张庆柱，神经药理学研究技术与方法，北京，人民卫生出版社，2005, 745-757
45 Shen L，Zhang J. Ginsenoside Rg1 increase ischemia-induced cell proliferation and survival in the dentate gyrus of adult gerbils[J]. Neurosci Lett. 2003，344(1):1-4
46 申丽红，张均田. 胎鼠神经干细胞培养方法的建立及药物对干细胞增殖的影响[J]. 药学学报.，38(10):735-738 2003
47 Shen L H，Zhang J T. Ginsenoside Rg1 promotes proliferation of hippocampal progenitor cells. Neurol Res[J].，26(4):422-428 2004
48 Shen L，Zhang J.NMDA receptor and iNOS are involved in the effects of ginsenoside Rg1 on hippocampal neurogenesis in ischemic gerbils[J]. Neurol Res. 2007，29(3):270-273
49 Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain，with special reference to persisting neurogenesis in the olfactory bulb[J]. J Comp Neurol. 1969，137(4):433-457
50 Altman J，Das G D. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats[J]. J Comp Neurol. 1965，124(3):319-335
51 Eriksson P S,Perfilieva E,Bjork-Eriksson T .Neurogenesis in the adult human hippocampus [J]. Nat Med. 1998:4 (11):1313-1317
52 Palmer T D，Ray J，Gage F H. FGF-2-responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain[J]. Mol Cell Neurosci. 1995，6(5):474-486
53 Palmer T D，Markakis E A，Willhoite A R，et al. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS[J]. J Neurosci. 1999，19(19):8487-8497
54 YamaTranscription factor expression and Notch-dependent regulation of neural progenitors in the adult rat spinal cord[J]. J Neurosci. 2001，21(24):9814-9823moto S,Naqao M,Suqimori M,et al.
55 Yamada M，Onodera M，Mizuno Y，et al. Neurogenesis in olfactory bulb identified by retroviral labeling in normal and 1-methyl-4-pheny-1，2，3，6-tetrahydropyridine-treated adult mice[J]. Neuroscience. 2004，124(1):173-181
56 Belluzzi O，Benedusi M，Ackman J，et al. Electrophysiological differentiation of new neurons in the olfactory bulb[J]. J Neurosci. 2003，23(32):10411-10418
57 Carlen M，Cassidy R M, Brismar H, et al. Functional integration of adult- born neurons[J]. Curr Biol. 2002，12 (7):606-608
58 Henriette van Praag , Alejandro F. Schinder , Brian R. Christie，et al. Functional neurogenesis in the adult hippocampus[J]. Nature. 2002，415(6875):1030-1034.
59 Morshead C M，Van Der Kooy D. Postmitotic death is the fate of constitutively proliferating cells in the subependymal layer of the adult mouse brain[J]. J Neurosci. 1992，12(1):249-256
60 Cameron H A，McKay R D. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus[J]. J Comp Neurol. 2001，435(4):406-417
61 Kato T，Yokouchi K, Fukushima N, et al. Continual replacement of newly-generated olfactory neurons in adult rats [J]. Neurosci Lett. 2001，307(1):17-20
62 Kuhn H G，Dickinson-Anson H，Gage F H，Neurogenesis in the dentate gyrus of the adult rat:age-related decrease of neuronal progenitor proliferation[J]. J Neurosci. 1996，16(6):2027-2033
63 Shors T J.Miesegaes G，Beylin A，et al. Neurogenesis in the adult is involved in the formation of trace memories[J]. Nature. 2001，410(6826):372-276
64 Haughey N J，Liu D，Nath A，et al. Disruption of neurogenesis in the subventricular zone of adult mice，and in human cortical neuronal precursor cells in culture，by amyloid betapeptide: implications for the pathogenesis of Alzheimer’s disease[J]. Neuromolecular Med. 2002，1(2):125-135
65 李君庆，张均田.细胞程序性死亡与疾病[J].中国药学杂志 1996，31(4):198-200
66 李君庆，李宇锴，段红，张均田.年龄及人参皂苷 Rg1对大鼠大脑皮层NO释放的影响[J].药学学报，1997，32(4):23-27
67 Li Junqing，Zhang Juntian.Inhibition of apoptosis by ginsenoside Rg1，In cultured cortical neurons[J]. Chin Med J (Engl). 1997，110(7):535-539
68 李君庆，张香阁，张均田.人参皂苷Rg1抗神经细胞凋亡作用机制的研究[J].药学学报，1997，32(6):406-410
69 Chen X C，Chen Y，Zhu Y G，et al. Protective effect of ginsenoside Rg1 against MPTP-induced apoptosis in mouse subtantia nigra neurons[J]. Acta Pharmacol Sin. 2002，23(9):829-834
70 Chen X C，Zhu Y G，Wang X Z，et al. Protective effect of ginsenoside Rg1 on dopamine-induced apoptosis in PC12 cells[J]. Acta Pharmacol Sin. 2001，22(8):673-678

[1]	ZHANG Xiang-yang. Neurocognitive Impairment in Schizophrenia: Clinical Correlates and Pathophysiological Mechanisms [J]. Acta Neuropharmacologica, 2018, 8(5): 89-90.
[2]	ZHU Min1, LI Ling-hai2. Advances in Research on Application of Anesthetics and Postoperative Cognitive Dysfunction in Patients [J]. Acta Neuropharmacologica, 2018, 8(3): 32-.
[3]	WANG Lun-zheng, XIE Wen-juan, TANG Tie-Shan. Neural Stem Cells, Adult Neurogenesis and Cell Therapy for Neurodegenerative Diseases [J]. Acta Neuropharmacologica, 2015, 5(3): 46-64.
[4]	CHU Shi-feng, ZHANG Jun-tian. A New Type of Anti-dementia Drug: The Chemistry, Biological Activities and Mechanism of Action of (-) Clausenamide [J]. Acta Neuropharmacologica, 2014, 4(6): 33-43.
[5]	CHEN Jiao, CHU Shi-feng, WANG Zhen-zhen, CHEN Nai-hong. Research Progress of GSK3 in the Pathophysiology of Depression Disorder [J]. Acta Neuropharmacologica, 2014, 4(5): 44-54.
[6]	WANG Ying, LIU Yu-gang, ZHANG Dan-shen. Animal Models of Alzheimer's Disease: a Review [J]. Acta Neuropharmacologica, 2014, 4(2): 27-38.
[7]	Tang Min-ke，Fan Yue，Liu Chang-suo，Zhang Jun-tian. Progress of The Mechanisms of Neuroprotective Effects of Salvianolic Acid B [J]. Acta Neuropharmacologica, 2014, 4(1): 1-10.
[8]	LIU Ting-ting, WANG Wen. Eph/ephrin Signaling Pathway in Brain Neurogenesis [J]. Acta Neuropharmacologica, 2014, 4(1): 25-28.
[9]	HE Na, YIN Ming, WANG Ze-jian. Progress in the Relationship of Adult Hippocampal Neurogenesis and Alzheime’s Disease [J]. Acta Neuropharmacologica, 2013, 3(6): 25-32.
[10]	LI Wei，LI Ting-ting，QI Sai-qing，ZHANG Gui-rong. Review on the Impact of Rapid Eye Movement Sleep Deprivation on Synaptic Plasticity and its Molecular Mechanisms [J]. Acta Neuropharmacologica, 2013, 3(4): 47-57.
[11]	Jin Can, ZHANG Dan-shen, CHEN Nai-hong. Research Advance in Relationship between Adult Hippocampal Neurogenesis and Mechanisms of Depression [J]. Acta Neuropharmacologica, 2013, 3(2): 58-64.
[12]	ZHANG Xia-wei,ZHANG Dan-shen. Progress in Understanding the Relevance of Learning and Memory to Estrogen and Glu-NMDA Receptor Pathway [J]. Acta Neuropharmacologica, 2011, 1(6): 48-59.
[13]	CHU Shi-feng, CHEN Nai-hong. Distinct Roles and Modulations of Synaptic and Extrasynaptic NMDA Receptors [J]. Acta Neuropharmacologica, 2011, 1(5): 40-48.