Comparative studies using the Morris water maze to assess spatial memory deficits in two transgenic mouse models of Alzheimer's disease.

Evaluation of the efficacy of novel therapeutics for potential treatment of Alzheimer's disease (AD) requires an animal model that develops age-related cognitive deficits reproducibly between independent groups of investigators. Herein we assessed comparative temporal changes in spatial memory function in two commercially available transgenic mouse models of AD using the Morris water maze (MWM), incorporating both visible and hidden platform training. Individual cohorts of cDNA-based 'line 85'-derived double-transgenic mice coexpressing the 'Swedish' mutation of amyloid precursor protein (APPSwe) and the presenillin 1 (PS1) 'dE9' mutation were assessed in the MWM at mean ages of 3.6, 9.3 and 14.8 months. We found significant deficits in spatial memory retention in APPSwe/PS1dE9 mice aged 3.6 months and robust deficits in spatial memory acquisition and retention in APPSwe/PS1dE9 mice aged 9.3 months, with a further significant decline by age 14.8 months. β-Amyloid deposits were present in brain sections by 7.25 months of age. In contrast, MWM studies with individual cohorts (aged 4-21 months) of single-transgenic genomic-based APPSwe mice expressing APPSwe on a yeast artificial chromosomal (YAC) construct showed no significant deficits in spatial memory acquisition until 21 months of age. There were no significant deficits in spatial memory retention up to 21 months of age and β-amyloid deposits were not present in brain sections up to 24 months of age. These data, generated using comprehensive study designs, show that APPSwe/PS1dE9 but not APPSwe YAC mice appear to provide a suitably robust model of AD for efficacy assessment of novel AD treatments in development.

Edwards SR ，Hamlin AS ，Marks N ，Coulson EJ ，Smith MT ... -  《-》

Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities.

Savonenko A ，Xu GM ，Melnikova T ，Morton JL ，Gonzales V ，Wong MP ，Price DL ，Tang F ，Markowska AL ，Borchelt DR ... -  《NEUROBIOLOGY OF DISEASE》

Visuo-spatial learning and memory deficits on the Barnes maze in the 16-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease.

O'Leary TP ，Brown RE 《-》

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 ... -  《-》

Changes in the brain and plasma Aβ peptide levels with age and its relationship with cognitive impairment in the APPswe/PS1dE9 mouse model of Alzheimer's disease.

Double transgenic mice expressing mutant amyloid precursor protein (APPswe) and mutant presenilin 1 (PS1dE9) are a model of Alzheimer-type amyloidosis and are widely used in experimental studies. In the present work, the relationships between brain and plasma amyloid-β peptide (Aβ) levels and cognitive impairments were examined in male APPswe/PS1dE9 double transgenic mice at different ages. When compared with non-transgenic littermates, APPswe/PS1dE9 mice exhibited significant learning deficits from the age of 6months (M6), which were aggravated at later stages of life (M8 and M12). Sporadic brain amyloid plaques were observed in mice as early as M3 and progressively increased in number and size up to M12. A similar increase was observed in brain insoluble Aβ levels as assessed by enzyme-linked immunosorbent assay (ELISA). In particular, the levels of brain insoluble Aβ peptides rose steeply from M4 to M6. Interestingly, this pronounced amyloid deposition was accompanied by a temporary fall in the concentration of brain soluble and membrane-bound Aβ peptides at M6 that rose again at M8 and M12. The plasma levels of Aβ40 and Aβ42 decreased with advancing age up to M8, when they stabilized at M12. This decrease in plasma Aβ levels coincided with the observed increase in insoluble brain Aβ levels. These results could be useful for developing plasma Aβ levels as possible biomarkers of the cerebral amyloidosis and provide advances in the knowledge of the Aβ peptide biochemical changes that occur in the brain of Alzheimer's disease patients.

Izco M ，Martínez P ，Corrales A ，Fandos N ，García S ，Insua D ，Montañes M ，Pérez-Grijalba V ，Rueda N ，Vidal V ，Martínez-Cué C ，Pesini P ，Sarasa M ... -  《-》