Multi-metric behavioral comparison of APPsw and P301L models for Alzheimer's disease: linkage of poorer cognitive performance to tau pathology in forebrain.

APPsw transgenic mice bearing the "Swedish" amyloid precursor protein (APP) mutation and JNPL3 transgenic mice bearing the P301L (Tau) mutation were compared to control non-transgenic (NT) mice in an extensive behavioral test battery administered between 5 and 8.5 months of age. APP mice were impaired in a variety of cognitive-based tasks prior to overt Abeta plaque development, making involvement of mutant APP overexpression and/or oligomeric Abeta assemblies most likely. Although Tau mice, as a group, were not impaired in any single behavioral measure, a collective assessment of behavioral measures through discriminant function analysis showed that Tau mice were impaired in overall behavioral (cognitive) performance. Moreover, correlation analyses involving Tau mice alone revealed linkage between poorer cognitive performance in all three water maze tasks and the number of neurofibrillary tangle (NFT)-containing neurons in neocortex and hippocampus. These findings indicate that: (1) APP mice show early and extensive cognitive impairment before evident Abeta deposition, and (2) the process or product of NFT formation in Tau mice is sufficient to deleteriously impact cognitive performance.

Arendash GW ，Lewis J ，Leighty RE ，McGowan E ，Cracchiolo JR ，Hutton M ，Garcia MF ... -  《BRAIN RESEARCH》

Lifelong immunization with human beta-amyloid (1-42) protects Alzheimer's transgenic mice against cognitive impairment throughout aging.

Jensen MT ，Mottin MD ，Cracchiolo JR ，Leighty RE ，Arendash GW ... -  《NEUROSCIENCE》

Use of multimetric statistical analysis to characterize and discriminate between the performance of four Alzheimer's transgenic mouse lines differing in Abeta deposition.

Leighty RE ，Nilsson LN ，Potter H ，Costa DA ，Low MA ，Bales KR ，Paul SM ，Arendash GW ... -  《BEHAVIOURAL BRAIN RESEARCH》

Progressive cognitive impairment and anxiety induction in the absence of plaque deposition in C57BL/6 inbred mice expressing transgenic amyloid precursor protein.

Numerous transgenic mouse models for Alzheimer's disease (AD) have been generated to recapitulate the histological pathogenesis and behavioral phenotypes of AD brain. However, none of the existing models exhibits the full spectrum of AD symptoms, nor have all of the traits mimicked by the developed animal models been successfully represented within a single mouse line, indicating that the development of transgenic lines showing new features of the AD-like brain should be explored. Here we report on a transgenic mouse line, named Tg-APP (Sw, V717F)/B6, that expresses the human amyloid precursor protein (APP) containing the Swedish and the V717F Indiana mutations in the brains of inbred C57BL/6 mice, designed to eliminate the potential phenotypic variations attributed to the compound genetic backgrounds adopted in most AD mouse models. The Tg-APP (Sw, V717F)/B6 mice expressed the transgene transcript, in the heterozygote state, at a level of 2.6 +/- 0.1 fold higher than that of endogenous mouse APP. However, no Abeta-plaque deposition was produced in the brain of the Tg-APP (Sw, V717F)/B6 mice up to 18 months of age. The Tg-APP(Sw, V717F)/B6 mice at 13-15 months showed reduced expression of calbindin and c-Fos in the brain. The Tg-APP (Sw, V717F)/B6 mice at 11-14 months displayed decreased motor coordination, learning and memory deficits, and severely increased anxiety. These phenotypes were not observed in the Tg-APP (Sw, V717F)/B6 mice at 5-7 months. Microarray analysis revealed altered expression, in the amygdala of the Tg-APP (Sw, V717F)/B6 mice, of genes previously implicated in anxiety. Taken together, these results suggest that the transgenic APP, or its derivatives, produces the age-dependent pathophysiology of the AD-like brain and that the progressive cognitive impairment and anxiety induction can proceed in the absence of visible Abeta-plaque deposition.

Lee KW ，Lee SH ，Kim H ，Song JS ，Yang SD ，Paik SG ，Han PL ... -  《JOURNAL OF NEUROSCIENCE RESEARCH》

A diet high in omega-3 fatty acids does not improve or protect cognitive performance in Alzheimer's transgenic mice.

Arendash GW ，Jensen MT ，Salem N Jr ，Hussein N ，Cracchiolo J ，Dickson A ，Leighty R ，Potter H ... -  《NEUROSCIENCE》