Amyloid β peptide as a physiological modulator of neuronal ‘A’-type K+ current

Plant, Leigh D.; Webster, Nicola J.; Boyle, John P.; Ramsden, Martin; Freir, Darragh B.; Peers, Chris; Pearson, Hugh A.

doi:10.1016/j.neurobiolaging.2005.09.038

Cited by 91 publications

(62 citation statements)

References 32 publications

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“…Alternatively, BACE2, which also cleaves at Asp1 (but with lower efficiency than BACE1) and is expressed in the brain (but at much lower levels than BACE1), may play a role in producing residual Aβ in BACE1 −/− ·5XFAD brain. Consistent with recent evidence suggesting potential physiological roles for Aβ peptides (Esteban, 2004;Kamenetz et al, 2003;Pearson and Peers, 2006;Plant et al, 2006;Yu et al, 2001), our findings favor the idea that normal levels of Aβ may be necessary for neuronal functions involved in learning and memory, although further investigation is required to elucidate potential underlying mechanisms.…”

Section: Discussionsupporting

confidence: 89%

BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

Ohno

Cole

Yasvoina

et al. 2007

Neurobiology of Disease

267

218

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Evidence suggests that β-amyloid (Aβ) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer's disease (AD). However, the causal link between Aβ and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have recently developed transgenic mice that overexpress human APP and PS1 with five familial AD mutations (5XFAD mice) and exhibit robust neuron death. Here, we demonstrate that genetic deletion of the β-secretase (BACE1) not only abrogates Aβ generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice. Importantly, BACE1 gene deletion also rescues memory deficits in 5XFAD mice. Our findings provide strong evidence that Aβ ultimately is responsible for neuron death in AD and validate the therapeutic potential of BACE1-inhibiting approaches for the treatment of AD.

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Section: Discussionsupporting

confidence: 89%

BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

Ohno

Cole

Yasvoina

et al. 2007

Neurobiology of Disease

267

218

View full text Add to dashboard Cite

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“…We hypothesize that disruption of neuronal membrane integrity by insertion of (proto-)fibrillar A␤ before plaque formation yields robust changes to V R . Subsequent disruption of, for instance, voltagedependent channel functions (Talley et al, 2003;Ye et al, 2003;Misonou et al, 2005;Plant et al, 2006;Lima et al, 2008) pertinent to maintain a stable, hyperpolarized plasmalemmal membrane potential may underscore sustained membrane depolarization. This notion is also consistent with the observations of lowered seizure thresholds after systemic challenge with pentylentetrazol not only in plaque-bearing APP transgenic mice (Palop et al, 2007) but also in those with elevated levels of soluble A␤ aggregates but no plaques (Del Vecchio et al, 2004;Palop et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Minkeviciene¹,

Rheims²,

Dobszay³

et al. 2009

J. Neurosci.

573

544

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Alzheimer's disease is associated with an increased risk of unprovoked seizures. However, the underlying mechanisms of seizure induction remain elusive. Here, we performed video-EEG recordings in mice carrying mutant human APPswe and PS1dE9 genes (APdE9 mice) and their wild-type littermates to determine the prevalence of unprovoked seizures. In two recording episodes at the onset of amyloid ␤ (A␤) pathogenesis (3 and 4.5 months of age), at least one unprovoked seizure was detected in 65% of APdE9 mice, of which 46% had multiple seizures and 38% had a generalized seizure. None of the wild-type mice had seizures. In a subset of APdE9 mice, seizure phenotype was associated with a loss of calbindin-D28k immunoreactivity in dentate granular cells and ectopic expression of neuropeptide Y in mossy fibers. In APdE9 mice, persistently decreased resting membrane potential in neocortical layer 2/3 pyramidal cells and dentate granule cells underpinned increased network excitability as identified by patch-clamp electrophysiology. At stimulus strengths evoking single-component EPSPs in wild-type littermates, APdE9 mice exhibited decreased action potential threshold and burst firing of pyramidal cells. Bath application (1 h) of A␤1-42 or A␤25-35 (proto-)fibrils but not oligomers induced significant membrane depolarization of pyramidal cells and increased the activity of excitatory cell populations as measured by extracellular field recordings in the juvenile rodent brain, confirming the pathogenic significance of bath-applied A␤ (proto-)fibrils. Overall, these data identify fibrillar A␤ as a pathogenic entity powerfully altering neuronal membrane properties such that hyperexcitability of pyramidal cells culminates in epileptiform activity.

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“…Indeed, there is good evidence for the normal function of beta amyloid in cellular processes (Plant, Boyle, Smith, Peers, & Pearson, 2003) and in fact, beta amyloid modulates potassium channels (Plant et al, 2005) -an important mediator of many forms of learning and memory (Giese et al, 1998;Nelson, Schreurs, & Alkon, 1999;Schrader, Anderson, Varga, Levy, & Sweatt, 2002;Schreurs, Gusev, Tomsic, Alkon, & Shi, 1998). It is certainly possible that by increasing the level of beta amyloid, the cholesterol diet facilitated HR conditioning by modulating cellular potassium channels and affecting neuronal excitability -a mechanism known to be involved in learning and memory (Johnston et al, 2003;Xu & Kang, 2005;Zhang & Linden, 2003).…”

Section: Discussionmentioning

confidence: 99%

Cholesterol enhances classical conditioning of the rabbit heart rate response

Schreurs

Smith-Bell

Darwish

et al. 2007

Behavioural Brain Research

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The cholesterol-fed rabbit is a model of atherosclerosis and has been proposed as an animal model of Alzheimer's disease. Feeding rabbits cholesterol has been shown to increase the number of beta amyloid immunoreactive neurons in the cortex. Addition of copper to the drinking water of cholesterol-fed rabbits can increase this number still further and may lead to plaque-like structures. Classical conditioning of the nictitating membrane response in cholesterol-fed rabbits is retarded in the presence of these plaque-like structures but may be facilitated in their absence. In a factorial design, rabbits fed 2% cholesterol or a normal diet (0% cholesterol) for 8 weeks with or without copper added to the drinking water were given trace classical conditioning using a tone and periorbital electrodermal stimulation to study the effects of cholesterol and copper on classical conditioning of heart rate and the nictitating membrane response. Cholesterol-fed rabbits showed significant facilitation of heart rate conditioning and conditioning-specific modification of heart rate relative to normal diet controls. Consistent with previous research, cholesterol had minimal effects on classical conditioning of the nictitating membrane response when periorbital electrodermal stimulation was used as the unconditioned stimulus. Immunohistochemical analysis showed a significant increase in the number of beta amyloid positive neurons in the cortex, hippocampus and amygdala of the cholesterol-fed rabbits. Supplementation of drinking water with copper increased the number of beta amyloid positive neurons in the cortex of cholesterol-fed rabbits but did not produce plaque-like structures or have a significant effect on heart rate conditioning. The data provide additional support for our finding that, in the absence of plaques, dietary cholesterol may facilitate learning and memory. Cholesterol enhances rabbit heart rate conditioningThe cholesterol-fed rabbit has been used as an animal model of atherosclerosis since 1913 when Anitchkow first demonstrated that a cholesterol diet induced vascular lesions (Bocan, 1998;Fan & Watanabe, 2000;Finking & Hanke, 1997;Moghadasian, 2002). More recently, the cholesterol-fed rabbit has been proposed as an animal model of Alzheimer's disease (Ghribi, Larsen, Schrag, & Herman, 2006;Sjogren, Mielke, Gustafson, Zandi, & Skoog, 2006 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Sparks, 1997;Sparks, Martin, Gross, & Hunsaker III, 2000;Zatta, Zambenedetti, Stella, & Licastro, 2002). Based on the observation that patients with heart disease had beta amyloid st...

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Amyloid β peptide as a physiological modulator of neuronal ‘A’-type K+ current

Cited by 91 publications

References 32 publications

BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

Cholesterol enhances classical conditioning of the rabbit heart rate response

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