Behavioral characterization of the Tg2576 transgenic model of Alzheimer's disease through 19 months

King, David L; Arendash, Gary W.

doi:10.1016/s0031-9384(02)00639-x

Cited by 210 publications

(170 citation statements)

References 40 publications

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“…6D), reflecting increased locomotor activity. These alterations are consistent with the reported behavioral deficits in Tg2576 mice (20,35). However, novel arm entries, time spent in the novel arm, and arm alteration were comparable between in Tg2576/CD36 0/0 mice and nontransgenic littermates or CD36 0/0 mice (P > 0.05), with reductions seen only at age 22 mo (Fig.…”

Section: Cd36 Deletion Counteracts Loss Of Vascular Lpr-1 and Zo-1 Insupporting

confidence: 90%

“…Finally, we used a two-trial spatial-memory task in a Y maze (20,33,34) to determine whether the reduced neurovascular dysfunction and CAA in Tg2576/CD36 0/0 mice are associated with improved cognitive performance. We chose the Y maze test for its high sensitivity to the behavioral dysfunction of Tg2576 mice (35). As described elsewhere (20), in the first trial (acquisition), mice were placed in the Y maze with the third arm blocked.…”

Section: Cd36 Deletion Counteracts Loss Of Vascular Lpr-1 and Zo-1 Inmentioning

confidence: 99%

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Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Park

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

133

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Deposition of amyloid-β (Aβ) in cerebral arteries, known as cerebral amyloid angiopathy (CAA), occurs both in the setting of Alzheimer's disease and independent of it, and can cause cerebrovascular insufficiency and cognitive deficits. The mechanisms leading to CAA have not been established, and no therapeutic targets have been identified. We investigated the role of CD36, an innate immunity receptor involved in Aβ trafficking, in the neurovascular dysfunction, cognitive deficits, and amyloid accumulation that occurs in mice expressing the Swedish mutation of the amyloid precursor protein (Tg2576). We found that Tg2576 mice lacking CD36 have a selective reduction in Aβ1-40 and CAA. This reduced vascular amyloid deposition was associated with preservation of the Aβ vascular clearance receptor LRP-1, and protection from the deleterious effects of Aβ on cerebral arterioles. These beneficial vascular effects were reflected by marked improvements in neurovascular regulation and cognitive performance. Our data suggest that CD36 promotes vascular amyloid deposition and the resulting cerebrovascular damage, leading to neurovascular dysfunction and cognitive deficits. These findings identify a previously unrecognized role of CD36 in the mechanisms of vascular amyloid deposition, and suggest that this scavenger receptor is a putative therapeutic target for CAA and related conditions. T here is increasing evidence that alterations in the structure and function of cerebral blood vessels contribute to the brain dysfunction underlying Alzheimer's disease (AD) (1, 2). Whereas resting cerebral blood flow (CBF) is reduced early in course of AD (3, 4), the increase in CBF induced by brain activity (functional hyperemia), a vital mechanism matching the metabolic demands of active neurons with the delivery of nutrients through blood flow, is suppressed (5, 6). With disease progression, deposition of amyloid-β (Aβ) in cerebral blood vessels, a condition known as cerebral amyloid angiopathy (CAA), damages cerebrovascular cells, weakens vessel walls, and disrupts vascular function further (7). CAA also occurs independent of AD and has emerged as a frequent cause of brain hemorrhage, silent infarct, and cognitive impairment (8, 9).Studies in mice overexpressing mutated forms of the amyloid precursor protein (APP) have demonstrated that Aβ peptides, especially Aβ1-40, which accumulates preferentially in cerebral blood vessels, alter cerebrovascular function, resulting in vasoconstriction, impaired functional hyperemia, and inability of the endothelium to regulate vascular tone (10-12).These studies have raised the possibility that Aβ, in addition to damaging neurons and glia, also threatens the cerebral blood supply and increases the brain's susceptibility to hypoxia-ischemia (1, 13). Furthermore, considering that vascular transport is a key pathway for clearance of Aβ from the brain (14), these vascular alterations also may enhance the accumulation of Aβ in brain and cerebral blood vessels.Converging evidence indicates that Aβ exerts i...

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Section: Cd36 Deletion Counteracts Loss Of Vascular Lpr-1 and Zo-1 Insupporting

confidence: 90%

Section: Cd36 Deletion Counteracts Loss Of Vascular Lpr-1 and Zo-1 Inmentioning

confidence: 99%

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Park

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

133

View full text Add to dashboard Cite

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“…This finding is in line with an earlier onset of LTP deficits in the dentate gyrus and dendritic spine loss in the CA1 region of the hippocampus (Jacobsen et al ., 2006). Impaired spatial learning, working memory and contextual fear conditioning were observed at the same age (King & Arendash, 2002) which is well before extracellular plaques appear in the brain of these mice starting in limbic and cortical structures at the age of 10 months (Hsiao et al ., 1996; Kawarabayashi et al ., 2001). We were also able to detect APP transgene expression in I5 mice which do not develop plaques but still show synaptic deficits later in age (Mucke et al ., 2000).…”

Section: Discussionmentioning

confidence: 96%

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

et al. 2016

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SummaryAlzheimer's disease (AD) is histopathologically characterized by neurodegeneration, the formation of intracellular neurofibrillary tangles and extracellular Aβ deposits that derive from proteolytic processing of the amyloid precursor protein (APP). As rodents do not normally develop Aβ pathology, various transgenic animal models of AD were designed to overexpress human APP with mutations favouring its amyloidogenic processing. However, these mouse models display tremendous differences in the spatial and temporal appearance of Aβ deposits, synaptic dysfunction, neurodegeneration and the manifestation of learning deficits which may be caused by age‐related and brain region‐specific differences in APP transgene levels. Consequentially, a comparative temporal and regional analysis of the pathological effects of Aβ in mouse brains is difficult complicating the validation of therapeutic AD treatment strategies in different mouse models. To date, no antibodies are available that properly discriminate endogenous rodent and transgenic human APP in brains of APP‐transgenic animals. Here, we developed and characterized rat monoclonal antibodies by immunohistochemistry and Western blot that detect human but not murine APP in brains of three APP‐transgenic mouse and one APP‐transgenic rat model. We observed remarkable differences in expression levels and brain region‐specific expression of human APP among the investigated transgenic mouse lines. This may explain the differences between APP‐transgenic models mentioned above. Furthermore, we provide compelling evidence that our new antibodies specifically detect endogenous human APP in immunocytochemistry, FACS and immunoprecipitation. Hence, we propose these antibodies as standard tool for monitoring expression of endogenous or transfected APP in human cells and APP expression in transgenic animals.

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“…In this study, we examined impaired learning and memory by three different methods: passive avoidance learning, object recognition task, and the Morris water maze. In these methods, successive object recognition tasks are available (Mouri et al, 2007) and the Morris water maze gives no influence on results of passive avoidance test (Yamada et al, 1999;King and Arendash, 2002). Thus, some experiments were performed using the same mice as shown in Figure 1, although a possibility cannot be ruled out that the passive avoidance test was influenced by the water-maze training.…”

Section: Discussionmentioning

confidence: 99%

Consumption of Molecular Hydrogen Prevents the Stress-Induced Impairments in Hippocampus-Dependent Learning Tasks during Chronic Physical Restraint in Mice

Nagata

Nakashima-Kamimura

Mikami

et al. 2008

Neuropsychopharmacol

227

182

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We have reported that hydrogen (H 2 ) acts as an efficient antioxidant by gaseous rapid diffusion. When water saturated with hydrogen (hydrogen water) was placed into the stomach of a rat, hydrogen was detected at several mM level in blood. Because hydrogen gas is unsuitable for continuous consumption, we investigated using mice whether drinking hydrogen water ad libitum, instead of inhaling hydrogen gas, prevents cognitive impairment by reducing oxidative stress. Chronic physical restraint stress to mice enhanced levels of oxidative stress markers, malondialdehyde and 4-hydroxy-2-nonenal, in the brain, and impaired learning and memory, as judged by three different methods: passive avoidance learning, object recognition task, and the Morris water maze. Consumption of hydrogen water ad libitum throughout the whole period suppressed the increase in the oxidative stress markers and prevented cognitive impairment, as judged by all three methods, whereas hydrogen water did not improve cognitive ability when no stress was provided. Neural proliferation in the dentate gyrus of the hippocampus was suppressed by restraint stress, as observed by 5-bromo-2 0 -deoxyuridine incorporation and Ki-67 immunostaining, proliferation markers. The consumption of hydrogen water ameliorated the reduced proliferation although the mechanistic link between the hydrogen-dependent changes in neurogenesis and cognitive impairments remains unclear. Thus, continuous consumption of hydrogen water reduces oxidative stress in the brain, and prevents the stress-induced decline in learning and memory caused by chronic physical restraint. Hydrogen water may be applicable for preventive use in cognitive or other neuronal disorders.

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Behavioral characterization of the Tg2576 transgenic model of Alzheimer's disease through 19 months

Cited by 210 publications

References 40 publications

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

Consumption of Molecular Hydrogen Prevents the Stress-Induced Impairments in Hippocampus-Dependent Learning Tasks during Chronic Physical Restraint in Mice

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