The Effect Of Low-fat Diet Or Statin Interventions On Behaviors And Brain A? Pathology Of Different-month Period APP/PS1 Double Transgenic Mice

Objective: To investigate the effect of Low-fat diet or statin intervention on behaviors and brain A? pathology from different-month period APP/PS1 double transgenic mice.Methods: Thirty-five APP/PS1 double transgenic mice weighted 20 to 25 g were randomly and equally assigned into the five groups according to different interventions and different onset times of intervention. One group just feed with regular diet as blank control group; BC group).Four intervention groups were divided into two statin- intervention groups fed with atorvastatin(30 mg/Kg/d) and two low-fat diet interventions groups fed with fodder containing 1.8% fat were,however, each two groups initiated intervention separately from 4-month age and 7-month age.All mice were kept in constant temperature, continuous day and night lighting, free feed,and were regularly tested body weight up to 9 month-age.Before slaughtered, all mice were carried out at least 3 times of Morris water maze test to evaluate the effect of different kinds of interventions and different onset times on behaviors, in which the escape latency period and time through the hidden platform were checked and recorded. Mice brain tissues and blood were obtained. All mice brain were split into two parts following the median line, one half just for pathologic analysis, the other half was extracted into homogenate and kept in- 70 ? after hippocampus isolated.Double antibody sandwich ELISA method was employed to quantitatively analyze the levels of A?1- 40, A?1-42, ?-and ?-secretases in hippocampus homogenates. Meanwhile, a monoclonal antibody to A?1-42(ab10148)and a new kind of semi-quantitative rating method for tissue A? plaque immuno-reactivity(TAPIR)were used to immunostain mice brain sections.At the same time, the Image Pro Plus 6.0 Image software was employed to measure the ratio of A? plaque area/tissue section area and the numbers of nerve cells.In order to evaluate the effect of interventions on brain A?pathology, all TAPIR findings were divided into the TAPIR positive(TAPIR+) group and the TAPIR strongly positive(TAPIR++) group according to the numbers of immunostaining-positive plaques, mice body weight, Morris water maze test results, intervention methods and onset times of interventions and intervention time were correlatively analyzed between the two TAPIRsubgroups.Results: Two mice dead before the ending of observations. The body weight showed no significant difference among the five groups. Also no significant difference found in Morris water maze test results, whether the escape latency period or the space exploration between intervention groups and the blank group.ELISA findings showed that the levels of A?1-42 from hippocampus homogenate of the elderly statin intervention group and elderly low-fat diet intervention group were significantly higher than the blank control group(16.32 ± 2.64 ng/ml; 16.76 ±2.87 ng/ml; P = 0.019; P=0.009),in that middle-aged statin intervention group was significantly lower than elderly low-fat diet group(P = 0.036). However, no significant differences in the levels of A?1-40 and ?- secretase existed in all of hippocampus homogenates(F =1.042; P =0.403), only with a significantly statistics difference among the levels of ?- secretase in all hippocampus homogenates(F = 2.758;P = 0.047), the concentration ranked respectively from high to low as: elderly-aged statin intervention group ?elderly-aged low-fat intervention group ?blank control group?middle-aged low fat intervention ?middle-aged statin intervention group.TAPIR findings showed that brain tissue A ? plaques were clearly immunostained by ab10148.Automatic image analysis software verified that a significantly higher number of total neurons in the cortex areas existed between the elderly-aged low-fat diet intervention group and the elderly statin intervention group(P = 0.001, 0.003, 0.005), compared with the blank control group. Unfortunately, no significant difference in TAPIR grading results appeared between the two kinds of interventions and the two kinds of intervention onset time(P = 0.466; P = 0.137),compared with the blank control group.Interestedly, the average body weight of TAPIR++ mice was significantly higher than of TAPIR+ mice(F = 4.44; P = 0.043), meanwhile, the average escape latency in TAPIR++ mice showed an insignificant prolonging tendency, compared with the TAPIR+ mice(F = 0.886; P = 0.354).Conclusions:1.Whether middle-aged or elderly-aged started intervention, whether low-fat diet or statin intervention, failed to improve the behaviors and brain A? pathology of APP/PS1 double transgenic mice.2.Elderly-aged statin intervention and low-fat diet intervention possibly increased A?42levels in mice hippocampus homogenates supported the hypothesis that too late intervention might deteriorate AD pathology.3.In combination with recent pleiotropic research results on statins, our data supported a potential protecting effect of atorvastatin on mice brain.