Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein

Berger-Sweeney, Joanne; McPhie, Donna L.; Arters, Jill; Greenan, Jane; Oster-Granite, Mary Lou; Neve, Rachael L.

doi:10.1016/s0169-328x(99)00014-5

Cited by 85 publications

(47 citation statements)

References 35 publications

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“…In this context, it is worth noting that C99 has intrinsic neurotoxic properties 12 and causes synaptic degeneration; 13 furthermore, C99 can impair long-term potentiation 14 and cognition. 15 The results from this study show that stress upregulates steady-state APP mRNA levels without inducing any change in APP protein levels. These findings, together with our observation that stress causes a significant increase in nicastrin levels, suggest that stress promotes APP misprocessing.…”

Section: Discussionmentioning

confidence: 58%

“…While the neurotoxic potency of Ab is well known, [9][10][11] other studies have demonstrated the neurotoxic and cognition-impairing potential of C99. [12][13][14][15] Furthermore, in a vicious cascade that characterizes AD, Ab interacts with its protein precursor (APP), an interaction that is suggested to contribute to the mechanism of Ab neurotoxicity. 16,17 Observations that a large percentage of AD patients display hypercortisolemia 18,19 suggest that glucocorticoids (GC) and stress may contribute to the development or maintenance of AD.…”

Section: Introductionmentioning

confidence: 99%

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The amyloidogenic potential and behavioral correlates of stress

et al. 2007

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Observations of elevated basal cortisol levels in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids (GC) may contribute to the development and/or maintenance of AD. Consistent with that hypothesis, we show that stress and GC provoke misprocessing of amyloid precursor peptide in the rat hippocampus and prefrontal cortex, resulting in increased levels of the peptide C-terminal fragment 99 (C99), whose further proteolytic cleavage results in the generation of amyloid-b (Ab). We also show that exogenous Ab can reproduce the effects of stress and GC on C99 production and that a history of stress strikingly potentiates the C99-inducing effects of Ab and GC. Previous work has indicated a role for Ab in disruption of synaptic function and cognitive behaviors, and AD patients reportedly show signs of heightened anxiety. Here, behavioral analysis revealed that like stress and GC, Ab administration causes spatial memory deficits that are exacerbated by stress and GC; additionally, Ab, stress and GC induced a state of hyperanxiety. Given that the intrinsic properties of C99 and Ab include neuroendangerment and behavioral impairment, our findings suggest a causal role for stress and GC in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy can have a cumulative impact on the course of AD development and progression.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

The amyloidogenic potential and behavioral correlates of stress

et al. 2007

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“…Because APP CTFs impair Ca 2ϩ homeostasis, long-term potentiation, and inflammatory processes (Yankner et al, 1989;Berger-Sweeney et al, 1999;Lahiri et al, 2002;Chang and Suh, 2005), their accumulation could contribute to neuronal dysfunction in AD. Indeed, mice with PS deficiency in forebrain neurons show age-dependent accumulation of APP CTFs and neurodegeneration (Herms et al, 2003;Saura et al, 2004), which because of the lack of ␥-secretase could not be attributed to toxic effects of A␤.…”

Section: Discussionmentioning

confidence: 99%

Loss of γ-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis

Tamboli¹,

Prager²,

Thal³

et al. 2008

J. Neurosci.

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Presenilins (PSs) are components of the ␥-secretase complex that mediates intramembranous cleavage of type I membrane proteins. We show that ␥-secretase is involved in the regulation of cellular lipoprotein uptake. Loss of ␥-secretase function decreased endocytosis of low-density lipoprotein (LDL) receptor. The decreased uptake of lipoproteins led to upregulation of cellular cholesterol biosynthesis by increased expression of CYP51 and enhanced metabolism of lanosterol. Genetic deletion of PS1 or transgenic expression of PS1 mutants that cause early-onset Alzheimer's disease led to accumulation of ␥-secretase substrates and mistargeting of adaptor proteins that regulate endocytosis of the LDL receptor. Consistent with decreased endocytosis of these receptors, PS1 mutant mice have elevated levels of apolipoprotein E in the brain. Thus, these data demonstrate a functional link between two major genetic factors that cause early-onset and late-onset Alzheimer's disease.

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“…To date, nine research groups have independently created transgenic mouse lines expressing various CTF forms of the human APP in the brain. Five of these lines showed either neuronal atrophy Oster-Granite et al, 1996;Nalbantoglu et al, 1997;Sato et al, 1997) or impaired learning (Nalbantoglu et al, 1997;Berger-Sweeney et al, 1999;Lalonde et al, 2002a) at age 12 -28 months, whereas the other four lines including the recent reported one did not display any obvious neuronal loss or cognitive impairment (Shoji et al, 1990;Sandhu et al, 1991;Araki et al, 1994;Sberna et al, 1998;Li et al, 1999;Rutten et al, 2003). Thus, the developed transgenic mice expressing CTFs showed conflicting results that ranged from no phenotype to AD-like pathogenesis.…”

Section: Introductionmentioning

confidence: 99%