β-Amyloid-(1–42) Impairs Activity-dependent cAMP-response Element-binding Protein Signaling in Neurons at Concentrations in Which Cell Survival Is Not Compromised

Tong, Liqi; Thornton, Phillip L.; Balázs, R.; Cotman, Carl W.

doi:10.1074/jbc.m010450200

Cited by 208 publications

(164 citation statements)

References 47 publications

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“…Here we show that A␤(25-35) treatment induces a reduction in p-CREB immunoreactivity in the temporal cortex, which could account for the lower sst2 mRNA levels. This finding is concordant with in vitro studies in which A␤(1-40) was shown to suppress CREB phosphorylation in cultured cortical neurons (Tong et al, 2001). Notwithstanding, other transcription factors might also be involved.…”

Section: Discussionsupporting

confidence: 81%

Minocycline provides protection against β-amyloid(25-35)-induced alterations of the somatostatin signaling pathway in the rat temporal cortex

2008

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Section: Discussionsupporting

confidence: 81%

Minocycline provides protection against β-amyloid(25-35)-induced alterations of the somatostatin signaling pathway in the rat temporal cortex

2008

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“…A history of depression is a risk factor for AD (Ownby et al, 2006), and other findings suggest that reduced activation of serotonin signaling pathways might promote synaptic dysfunction and neuronal death in AD (reviewed by Mattson et al, 2004). For example, serotonin may enhance synaptic plasticity by activating cyclic AMP response element-binding protein (CREB) and up-regulating the expression of brain-derived neurotrophic factor (BDNF) (reviewed by Pang and Lu, 2004), and this signaling mechanism may be compromised in AD (Tong et al, 2001). Serotonin-selective reuptake inhibitors are widely prescribed for the treatment of clinical depression and anxiety disorders (Wagstaff et al, 2002;Bourin, 2003), but may also have therapeutic potential as neuroprotective agents (Sanchez et al, 2001;Duan et al, 2004).…”

Section: Introductionmentioning

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

163

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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“…Increased A␤ levels may also inhibit the expression of normal levels of ␥-secretase, because A␤ negatively regulates CREdependent gene expression, and expression of the genes encoding both PS1 and the essential ␥-secretase subunit Pen-2 is CRE-dependent (51)(52)(53). In support of a role for reduced PS expression in AD pathogenesis, PSEN1 promoter polymorphisms that reduce PS1 expression have been reported as risk factors for sporadic AD (54,55).…”

Section: Is a Pathogenic Mechanism Based On Loss Of Ps Function Compamentioning

confidence: 99%

“…Alternatively, loss of PS function and increased A␤ production may converge at common downstream signaling pathways that are required for synaptic plasticity and neuronal survival. For example, both PS inactivation and increased A␤ lead to reductions in synaptic NMDA receptors and CRE-dependent gene expression (4,51,52,56).…”

Section: Is a Pathogenic Mechanism Based On Loss Of Ps Function Compamentioning

confidence: 99%

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Shen

Kelleher

2007

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

431

358

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Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of ␤-amyloid (A␤) peptides, particularly A␤42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of A␤ have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance A␤42 production, they typically reduce A␤40 generation and impair other PS-dependent activities. Third, ␥-secretase inhibitors can enhance the production of A␤42 while blocking other ␥-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that A␤42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of ␥-secretase.A lzheimer's disease (AD) is an age-related neurodegenerative dementia and is the most common cause of both neurodegeneration and dementia. Neurodegenerative dementias are characterized clinically by progressive impairment of cognitive abilities, which most prominently affects memory in AD. Neuronal and synaptic loss is the essential neuropathological feature common to different forms of neurodegenerative dementias, including AD, frontotemporal dementia (FTD) and Lewy body dementia (LBD). These diseases are distinguished neuropathologically by characteristic patterns of abnormal protein aggregation, such as the presence in the AD brain of cerebral cortical amyloid plaques and neurofibrillary tangles (NFTs). Extracellular amyloid plaques consist primarily of 40-to 42-residue ␤-amyloid (A␤) peptides (A␤40 and A␤42) derived from proteolytic processing of the amyloid precursor protein (APP). NFTs are intraneuronal inclusions composed of hyperphosphorylated forms of the microtubule-associated protein tau.Research on AD has been greatly stimulated by the identification of causative mutations in the genes encoding APP and presenilins (PS1 and PS2). Dominantly inherited missense mutations in APP increase the production of A␤ peptides and account for Ϸ10% of mutations identified in familial AD (FAD). PSs harbor Ϸ90% of identified FAD mutations, and many of these mutations increase the relative production of A␤42 peptides. The prevailing amyloid hypothesis posits that accumulation of A␤ peptides, particularly the more hydrophobic and aggregation-prone A␤42, triggers a pathogenic cascade, leading to neurodegeneration in AD (1). However, a...

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β-Amyloid-(1–42) Impairs Activity-dependent cAMP-response Element-binding Protein Signaling in Neurons at Concentrations in Which Cell Survival Is Not Compromised

Cited by 208 publications

References 47 publications

Minocycline provides protection against β-amyloid(25-35)-induced alterations of the somatostatin signaling pathway in the rat temporal cortex

Minocycline provides protection against β-amyloid(25-35)-induced alterations of the somatostatin signaling pathway in the rat temporal cortex

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

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

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