Sensorimotor gating and memory deficits in an APP/PS1 double transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive deterioration and neuropsychiatric symptoms. Sensorimotor gating deficit has been identified in neuropsychiatric diseases. The aim of the present study was to evaluate the possible sensorimotor gating deficit and its correlation to memory impairment and cerebral β-amyloid (Aβ) plaque deposits in an amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mouse model of AD. The sensorimotor gating in 3-, 7- and-22-month-old non-transgenic and transgenic mice was evaluated in a prepulse inhibition (PPI) task. Results revealed that the PPI was lower in the 7- and 22-month-old transgenic mice compared with the age-matched control, while the response to startle pulse-alone in the transgenic and non-transgenic mice was comparable. Congo red staining showed that Aβ neuropathology of transgenic mice aggravated with age, and the 3-month-old transgenic mice started to have minimum brain Aβ plaques, corresponding to the early stage of AD phenotype. Furthermore, memory impairment in the 7-month-old transgenic mice was detected in a water maze test. These results suggest that the sensorimotor gating is impaired with the progressing of AD phenotype, and its deficit may be correlated to cerebral Aβ neuropathology and memory impairment in the APP/PS1 transgenic mouse model of AD.

Wang H ，He J ，Zhang R ，Zhu S ，Wang J ，Kong L ，Tan Q ，Li XM ... -  《-》

Effects of accelerated senescence on learning and memory, locomotion and anxiety-like behavior in APP/PS1 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a deficit in motor and spatial learning-memory and alteration of non-cognitive behavior. The generation of transgenic mice with presence of AD pathologies that cause learning and memory deficits has led to improved understanding of the behavioral and pathophysiological processes underlying AD. A novel APP/PS1 mouse model in the senescence accelerated mouse prone 8 (SAMP8) background--SAMP8 APP/PS1 was generated. To assess the behavioral and other AD-related changes in this SAMP8 APP/PS1 model, the present report covers a phenotypical analysis of this model for working memory, spatial memory, motor performance and anxiety-like behavior. SAMP8 APP/PS1 mice showed motor and spatial memory impairments, together with an increase of locomotor activity and lower anxiety-like behavior at 9months old. In contrast, C57 APP/PS1 and SAMP8 wild type mice were inconspicuous in all of these tasks and properties except C57 APP/PS1 mice which showed motor memory impairment in the shuttle box task at 9 months old. Standard senescence-associated beta-galactosidase (SA-beta-GAL) staining and amyloid beta (Aβ) immunohistochemistry showed more severe pathological changes in the SAMP8 APP/PS1 mice. SAMP8 APP/PS1 mice exhibited earlier deficits in their non-cognitive and cognitive behaviors which are coincident in the AD patient and the results suggest that this new type of mice might be a better model for studying the age-related dementia of the Alzheimer type and for assessing the potential therapeutic agents for AD.

Lok K ，Zhao H ，Zhang C ，He N ，Shen H ，Wang Z ，Zhao W ，Yin M ... -  《-》

Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1.

Ohno M ，Chang L ，Tseng W ，Oakley H ，Citron M ，Klein WL ，Vassar R ，Disterhoft JF ... -  《EUROPEAN JOURNAL OF NEUROSCIENCE》

Soluble Aβ levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease.

Amyloid-beta peptide (Aβ) is believed to be central in the pathogenesis of Alzheimer's disease (AD) characterized by cognitive deficits. However, it remains uncertain which form(s) of Aβ pathology is responsible for the cognitive deficits in AD. In the present study, the cognitive deficits and the profiles of Aβ pathology were characterized in the 12-month-old APPswe/PS1dE9 double transgenic mice, and their correlations were examined. Compared with non-transgenic littermates, the middle-aged APPswe/PS1dE9 mice exhibited spatial learning and memory deficits in the water maze test and long-term contextual memory deficits in the step-down passive avoidance test. Among the middle-aged APPswe/PS1dE9 mice, hippocampal soluble Aβ1-40 and Aβ1-42 levels were highly correlated with spatial learning deficits and long-term contextual memory deficits, as well as cortical and hippocampal soluble Aβ1-40 and Aβ1-42 levels were strongly correlated with spatial memory deficits. By contrast, no significant correlations were observed between three measures of cognitive functions and amyloid plaque burden (total Aβ plaque load and fibrillar Aβ plaque load), total Aβ levels (Aβ1-40 and Aβ1-42), as well as insoluble Aβ levels (Aβ1-40 and Aβ1-42). Stepwise multiple regression analysis identified hippocampal soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial learning deficits and the long-term contextual memory deficits, as well as hippocampal and cortical soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial memory deficits in transgenic mice. These results demonstrate that cognitive deficits are highly related to the levels of soluble Aβ in middle-aged APPswe/PS1dE9 mice, in which soluble Aβ levels are only a tiny fraction of the amount of total Aβ levels. Consequently, our findings provide further evidence that soluble Aβ might primarily contribute to cognitive deficits in AD, suggesting that reducing the levels of soluble Aβ species would be a therapeutic intervention for AD patients even with large deposits of aggregated, insoluble Aβ.

Zhang W ，Hao J ，Liu R ，Zhang Z ，Lei G ，Su C ，Miao J ，Li Z ... -  《-》

Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer's disease.

Increasing evidence indicates that a disturbance of normal iron homeostasis and an amyloid-β (Aβ)-iron interaction may contribute to the pathology of Alzheimer's disease (AD), whereas iron chelation could be an effective therapeutic intervention. In the present study, transgenic mice expressing amyloid precursor protein (APP) and presenilin 1 and watered with high-dose iron served as a model of AD. We evaluated the effects of intranasal administration of the high-affinity iron chelator deferoxamine (DFO) on Aβ neuropathology and spatial learning and memory deficits created in this AD model. The effects of Fe, DFO, and combined treatments were also evaluated in vitro using SHSY-5Y cells overexpressing the human APP Swedish mutation. In vivo, no significant differences in the brain concentrations of iron, copper, or zinc were found among the treatment groups. We found that high-dose iron (deionized water containing 10 mg/mL FeCl(3)) administered to transgenic mice increased protein expression and phosphorylation of APP695, enhanced amyloidogenic APP cleavage and Aβ deposition, and impaired spatial learning and memory. Chelation of iron via intranasal administration of DFO (200 mg/kg once every other day for 90 days) inhibited iron-induced amyloidogenic APP processing and reversed behavioral alterations. DFO treatment reduced the expression and phosphorylation of APP protein by shifting the processing of APP to the nonamyloidogenic pathway, and the reduction was accompanied by attenuating the Aβ burden, and then significantly promoted memory retention in APP/PS1 mice. The effects of DFO on iron-induced amyloidogenic APP cleavage were further confirmed in vitro. Collectively, the present data suggest that intranasal DFO treatment may be useful in AD, and amelioration of iron homeostasis is a potential strategy for prevention and treatment of this disease.

Guo C ，Wang T ，Zheng W ，Shan ZY ，Teng WP ，Wang ZY ... -  《-》