Correlation between cognitive deficits and Aβ deposits in transgenic APP+PS1 mice

Gordon, Marcia N.; King, David L; Diamond, David M.; Jantzen, Paul T.; Boyett, Kristal V; Hope, Caroline E.; Hatcher, Jaime M.; DiCarlo, Giovanni; Gottschall, W.Paul E; Morgan, Dave; Arendash, Gary W.

doi:10.1016/s0197-4580(00)00249-9

Cited by 168 publications

(124 citation statements)

References 46 publications

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“…Sham-treated AD mice exhibited poor recognition of the Y-maze novel arm (33% entry to novel arm, Fig. 3B), demonstrating impaired cognitive performance consistent with previous studies (29,30). By contrast, the Cu II (gtsm)-treated mice showed significantly improved cognitive performance with 48% entry to the novel arm ( Fig.…”

Section: Resultssupporting

confidence: 86%

Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Crouch

Hung²,

Adlard³

et al. 2009

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

246

268

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Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-␤ (A␤) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3␤ (GSK3␤) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3␤. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3␤ through activation of an Akt signaling pathway. Our lead compound Cu II (gtsm) significantly inhibited GSK3␤ in the brains of APP/PS1 transgenic AD model mice. Cu II (gtsm) also decreased the abundance of A␤ trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvement in the Y-maze correlated directly with decreased A␤ trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic A␤ trimers and phosphorylated tau.Alzheimer's disease ͉ bioinorganic chemistry ͉ glycogen synthase kinase ͉ therapeutic ͉ animal model A lzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by impaired cognitive performance and pathologically by cerebral deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. Amyloid plaques in AD contain aggregated forms of the 39-to 43-aa amyloid-␤ peptide (A␤) and A␤ is strongly implicated as a causative agent responsible for cognitive failure in AD. A diverse range of mechanisms for A␤ toxicity has been reported (1). A␤ is produced from the amyloid precursor protein (APP) (2-5) and readily aggregates to form insoluble, high-molecular-mass amyloid structures. Intermediates on the A␤ aggregation pathway, primarily low-molecular-mass oligomers such as dimers and trimers, exhibit the greatest neurotoxicity (6-8). In addition to A␤ oligomers, aberrantly phosphor ylated microtubuleassociated protein tau is also associated with cognitive decline in AD (9). Intracellular neurofibrillary tangles in the AD brain contain hyperphosphorylated tau, and A␤ induced cognitive deficits characteristic of AD transgenic mice are attenuated by decreasing levels of endogenous tau (10).It is now widely recognized that a truly effective therapeutic compound for treating AD needs to attenuate both the A␤-and tau-mediated pathologies. Recent positive outcomes for PBT2 in clinical and preclinical trials are therefore pertinent. Lannfelt et al.(11) demonstrated in phase IIa clinical trials that PBT2 lowers plasma A␤ levels and attenuates cognitive decline, and Adlard et al. (12) have shown that PBT2 decreases interstitial A␤ and phosphorylated tau in the brains of AD model mice. PBT2 is a secondgeneration 8-OH quinoline, which, unlike its predecessor clioquinol, lacks iodine and was selected for clinical development because of its easier chemical synthesis, higher solubility, and increased blood-brain barrier perme...

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Section: Resultssupporting

confidence: 86%

Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Crouch

Hung²,

Adlard³

et al. 2009

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

246

268

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“…Deficits in performance in tests of learning and memory have been documented in studies of several transgenic lines of APP mutant and APP/presenilin-1 double-mutant mice (Hsiao et al, 1996;Morgan et al, 2000;Gordon et al, 2001;Kotilinek et al, 2002). These deficits typically become evident prior to the overt deposition of Aβ and then intensify as Aβ pathology progresses.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Nelson

Guo

Halagappa

et al. 2007

Experimental Neurology

162

133

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A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7 month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Aβ) and numbers of Aβ immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model, suggests that such drugs administered prophylactically might retard the development of AD in humans.

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“…They also found a nonprogressive and profound impairment in balance beam performance and increased y-maze arm entries, indicative of generalized heightened activity. Gordon et al (2001) also assessed PSAPP spatial performance in the radial arm water maze at approximately 15-16 months of age. A PSAPP deficit in this task was found and also seems to be progressive, measurable in older mice but not at 5-7 (Arendash et al, 2001) or 11-12 months of age (Morgan et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…The PSAPP analyzed in our study demonstrated aberrant behavior whenever (even mildly) stressed at both ages: frequent rapid circle-running, exaggerated startle, and increased aggression as compared to wildtype. Regrettably, we did not quantify this behavior, although it may be apparent in the behavioral measures taken by Arendash et al (2001), epitomized by the progressively increasing open field activity and decreasing agility, and the stable impairment on other sensorimotor and anxiety-based assessments. It is also possible that these anxiety-based effects are impacting spatial memory performance (Diamond et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…The increased FDG uptake may indicate a mechanism to compensate for the visuospatial challenges the mice apparently develop, related to the retrosplenial cingulate dysfunction. It is also possible that the progressive amyloid burden is interacting with a genetic propensity of C57B6 mice (a component of the PSAPP background) to develop primary progressive auditory degeneration (Willott et al, 1993), but sensorimotor testing does not bear this out (Gordon et al, 2001). …”

Section: Discussionmentioning

confidence: 99%

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Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

2006

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In parallel to imaging studies in humans with Alzheimer's disease (AD), we have mapped brain metabolic activity in transgenic mouse models of AD. Our aim in both is to provide new surrogate markers of progression to help clarify disease mechanisms and rapidly screen candidate therapeutics. Since previous findings of preferential reductions in posterior cingulate glucose metabolism may have been confounded by morphological abnormalities in previously studied "PDAPP" transgenic mice, we first assessed hippocampal and callosal anatomy in PSAPP (PS1×APP) mice, another transgenic mouse model of AD, and found no major abnormalities. We then used fluorodeoxyglucose (FDG) autoradiography in older and younger PSAPP and wildtype mice to assess the functional state of 56 regions-of-interest across group, age and increasing amyloid load. Reductions in FDG uptake in aged transgenic mice, with significant interactions between group and age, were found in retrosplenial cingulate gyrus, found to be metabolically affected in persons affected by or at risk for AD, and in brain regions known to participate with retrosplenial cingulate in networks contributing to spatial learning deficits found in these animals. Like patients with AD, PSAPP mice have agerelated metabolic reductions in posterior cingulate cortex, a finding that does not appear to be related to morphological abnormalities. If longitudinal studies support these progressive and preferential reductions in retrosplenial metabolism in PSAPP mice, these reductions could provide an indicator of disease progression, help bridge the gap between human and animal studies of AD, and aid in clarification of disease mechanisms and screening of promising treatments.

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Correlation between cognitive deficits and Aβ deposits in transgenic APP+PS1 mice

Cited by 168 publications

References 46 publications

Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

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