The improvement effect of scFv17 on the gait of triple-transgenic mice

doi:10.12047/j.cjap.5656.2018.089

Abstract

Abstract: Objective: To observe the gait changes of Alzheimer's disease PS1M146V/APPswe/tauP301L triple-transgenic (3xTg-AD) mice and to investigate the improvement effect of single chain variable domain antibody fragment 17 (scFv17) on the gait.Methods: In the present study, a selection of 6-month-old 3xTg-AD mice (n=18) and C57BL/6 wild-type mice (n=24) was performed. First, we observed their gait changes and found that the gait of 12-month-old 3xTg-AD mice was severely damaged. Then, the two groups of mice were randomly divided into four groups:WT+PBS(n=12), WT+scFv17(n=12), 3xTg-AD+PBS(n=9) and 3xTg-AD+scFv17(n=9). The gait behavior test and pathological test were performed after 12 weeks'continuous administration of scFv17 (1.5 mg/kg) or an equal volume of PBS (0.01 mol/L) by nasal gavage twice a week. Results: Compared with the same month old wild type mice, the rear track width of 12 month old 3xTg-AD mice was increased(P<0.01), swing time percent was decreased (P<0.01), stance time percent was increased(P<0.01), so the ability of movement coordination and balance was seriously damaged. ScFv17 could improve the coordination and balance ability of 12 month old 3xTg-AD mice(P<0.01). The morphological structure of 3xTg-AD mice cerebellar Purkinje cells was improved. The treatment of scFv17 increased the Nissl body number of the cerebellar Purkinje cells of 3xTg-AD mice (P<0.01). scFv17 reduced the amyloid β protein (Aβ) plaques in the cerebellar cortex of 3xTg-AD mice (P<0.01), and scFv17 reduced the intracellular neurofibrillary tangles (NFT) of the cerebellar Purkinje cells of the 3xTg-AD mice (P<0.01). Conclusion: The coordination and balance ability of 3xTg-AD mice was significantly impaired. ScFv17 can improve gait behaviour in the 3xTg-AD significantly.The mechanism may be related to the improvement of the structure and protein function of cerebellar Purkinje cells, and the eliminating of the Aβ plaques and the neurofibrillary tangles.

Key words: 3xTg-AD mice, gait, cerebellum, scFv17

WANG Ting, CAO Yue, HU Meng-ming, ZHANG Xiu-min, DONG Xue-fan, QI Jin-shun, ZHANG Jun, YANG Wei. The improvement effect of scFv17 on the gait of triple-transgenic mice[J]. CJAP, 2018, 34(5): 389-395.

References

[1] Realdon O, Rossetto F, Nalin M, et al. Technology-enhanced multi-domain at home continuum of care program with respect to usual care for people with cognitive impairment:the Ability-TelerehABILITation study protocol for a randomized controlled trial[J]. BMC Psychiatry, 2016, 16(1):425.
[2] Blennow K, Hampel H, Weiner M, et al. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease[J]. Nat Rev Neurol, 2010, 6(3):131-144.
[3] Alexander NB, Mollo JM, Giordani B, et al. Maintenance of balance, gait patterns, and obstacle clearance in Alzheimer's disease[J]. Neurology, 1995, 45(5):908-914.
[4] O'Keeffe ST, Kazeem H, Philpott RM, et al. Gait disturbance in Alzheimer's disease:a clinical study[J]. Age Ageing, 1996, 25(4):313-316.
[5] Buchner DM, Larson EB. Falls and fractures in patients with Alzheimer-type dementia[J]. JAMA, 1987, 257(11):1492-1495.
[6] Visser H. Gait and balance in senile dementia of Alzheimer's type[J]. Age Ageing, 1983, 12(4):296-301.
[7] 张胜威, 董世芬, 武汀, 等. APP/PS1双转基因小鼠认知功能和实时步态行为的相关性[J]. 中国比较医学杂志, 2014(5):19-24.
[8] Stover KR, Campbell MA, Van Winssen CM, et al. Analysis of motor function in 6-month-old male and female 3xTg-AD mice[J]. Behav Brain Res, 2015, 281:16-23.
[9] Selkoe DJ. Normal and abnormal biology of the beta-amyloid precursor protein[J]. Annu Rev Neurosci, 1994, 17:489-517.
[10] Li YT, Woodruff-Pak DS, Trojanowski JQ. Amyloid plaques in cerebellar cortex and the integrity of Purkinje cell dendrites[J]. Neurobiol Aging, 1994, 15(1):1-9.
[11] Bas O, Acer N, Mas N, et al. Stereological evaluation of the volume and volume fraction of intracranial structures in magnetic resonance images of patients with Alzheimer's disease[J]. Ann Anat, 2009, 191(2):186-195.
[12] Fukutani Y, Cairns NJ, Rossor MN, et al. Cerebellar pathology in sporadic and familial Alzheimer's disease including APP 717(Val-->Ile) mutation cases:a morphometric investigation[J]. J Neurol Sci, 1997, 149(2):177-184.
[13] Sarna JR, Hawkes R. Patterned Purkinje cell death in the cerebellum[J]. Prog Neurobiol, 2003, 70(6):473-507.
[14] Traka M, Millen KJ, Collins D, et al. WDR81 is necessary for purkinje and photoreceptor cell survival[J]. J Neurosci, 2013, 33(16):6834-6844.
[15] Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease:an appraisal for the development of therapeutics[J]. Nat Rev Drug Discov, 2011, 10(9):698-712.
[16] Boluda S, Toledo JB, Irwin DJ, et al. A comparison of Abeta amyloid pathology staging systems and correlation with clinical diagnosis[J]. Acta Neuropathol, 2014, 128(4):543-550.
[17] Liu YH, Bu XL, Liang CR,et al. An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta:the dust-raising effect[J]. J Neuroinflammation, 2015, 12:153.
[18] Wooley CM, Xing S, Burgess RW, et al. Age, experience and genetic background influence treadmill walking in mice[J]. Physiol Behav, 2009, 96(2):350-361.
[19] Pedroso RV, Coelho FG, Santos-Galduroz RF, et al. Balance, executive functions and falls in elderly with Alzheimer's disease (AD):a longitudinal study[J]. Arch Gerontol Geriatr, 2012, 54(2):348-351.
[20] Nadkarni NK, Mawji E, McIlroy WE, et al. Spatial and temporal gait parameters in Alzheimer's disease and aging[J]. Gait Posture, 2009, 30(4):452-454.
[21] Sepulveda-Falla D, Matschke J, Bernreuther C, et al. Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer's disease[J]. Brain Pathol, 2011, 21(4):452-463.
[22] Shimada H, Ataka S, Tomiyama T, et al. Clinical course of patients with familial early-onset Alzheimer's disease potentially lacking senile plaques bearing the E693Delta mutation in amyloid precursor protein[J]. Dement Geriatr Cogn Disord, 2011, 32(1):45-54.
[23] Ordonez-Gutierrez L, Fernandez-Perez I, Herrera JL, et al. AbetaPP/PS1 transgenic mice show sex differences in the cerebellum associated with aging[J]. J Alzheimers Dis, 2016, 54(2):645-656.
[24] Frost JL, Liu B, Kleinschmidt M, et al. Passive immunization against pyroglutamate-3 amyloid-beta reduces plaque burden in Alzheimer-like transgenic mice:a pilot study[J]. Neurodegener Dis, 2012, 10(1-4):265-270.
[25] Esquerda-Canals G, Marti J, Rivera-Hernandez G, et al. Loss of deep cerebellar nuclei neurons in the 3xTg-AD mice and protection by an anti-amyloid beta antibody fragment[J]. MAbs, 2013, 5(5):660-664.
[26] Nie J, Tian Y, Zhang Y, et al. Dendrobium alkaloids prevent Abeta_25-35-induced neuronal and synaptic loss via promoting neurotrophic factors expression in mice[J]. PeerJ, 2016, 4:e2739.
[27] Li J, Wen PY, Li WW, et al. Upregulation effects of Tanshinone ⅡA on the expressions of NeuN, Nissl body, and IkappaB and downregulation effects on the expressions of GFAP and NF-kappaB in the brain tissues of rat models of Alzheimer's disease[J]. Neuroreport, 2015, 26(13):758-766.
[28] Cao Y, Xiao Y, Ravid R, et al. Changed clathrin regulatory proteins in the brains of Alzheimer's disease patients and animal models[J]. J Alzheimers Dis, 2010, 22(1):329-342.
[29] Walsh DT, Montero RM, Bresciani LG, et al. Amyloid-beta peptide is toxic to neurons in vivo via indirect mechanisms[J]. Neurobiol Dis, 2002, 10(1):20-27.