Amyloid Precursor Protein Regulates Ca<sub>v</sub>1.2 L-type Calcium Channel Levels and Function to Influence GABAergic Short-Term Plasticity

Yang, Li; Wang, Zilai; Wang, Baiping; Justice, Nicholas J.; Zheng, Hui

doi:10.1523/jneurosci.4104-09.2009

Cited by 102 publications

(111 citation statements)

References 53 publications

(67 reference statements)

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“…The results with currentclamp recording and Ca 2ϩ fluorometry combined together (Fig. 3) (Ueda et al, 1997;MacManus et al, 2000) and APP directly binds and modulates VDCC (Yang et al, 2009) (Fig. 4 A, B).…”

Section: Resultsmentioning

confidence: 95%

Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a

Yamamoto¹,

Ueta²,

Wang³

et al. 2011

J. Neurosci.

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It is proposed that intracellular amyloid-␤ (A␤), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular A␤ affects neuronal properties. This was done by injecting A␤ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular A␤ is accumulated innately. In rats, intracellular application of a mixed A␤ 1-42 preparation containing both oligomers and monomers, but not a monomeric preparation of A␤ 1-40 , broadened spike width and augmented Ca 2ϩ influx via voltage-dependent Ca 2ϩ channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca 2ϩ -activated K ϩ (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca 2ϩ influx was caused by elongated spike duration, but not attributable to direct Ca 2ϩ channel modulation by A␤ 1-42 . The A␤ 1-42 -induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by A␤ 1-42 , which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the A␤ 1-42 effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular A␤ 1-42 is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.

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Section: Resultsmentioning

confidence: 95%

Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a

Yamamoto¹,

Ueta²,

Wang³

et al. 2011

J. Neurosci.

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“…This may involve, as hypothesized ), a reduction in feedback suppression mediated by presynaptic GABA B autoreceptors (but see below Yang et al 2009). Although the molecular mechanisms of these alterations remain to be determined, these studies indicate that defects in Ca 2þ -handling, synaptic plasticity and/or neuronal network properties, rather than gross structural changes, cause functional impairments of APP knockout mice.…”

Section: App/aplp Single Knockout Micementioning

confidence: 88%

Physiological Functions of APP Family Proteins

Müller¹,

Zheng²

2011

Cold Spring Harbor Perspectives in Medicine

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262

235

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Biochemical and genetic evidence establishes a central role of the amyloid precursor protein (APP) in Alzheimer disease (AD) pathogenesis. Biochemically, deposition of the b-amyloid (Ab) peptides produced from proteolytic processing of APP forms the defining pathological hallmark of AD; genetically, both point mutations and duplications of wild-type APP are linked to a subset of early onset of familial AD (FAD) and cerebral amyloid angiopathy. As such, the biological functions of APP and its processing products have been the subject of intense investigation, and the past 20þ years of research have met with both excitement and challenges. This article will review the current understanding of the physiological functions of APP in the context of APP family members.

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“…Electrophysiology studies show that these mice are also defective in long-term potentiation (LTP), which is associated with attenuated paired-pulse depression of GABA-mediated inhibitory postsynaptic currents [44]. Recently, APP was found to be involved in the regulation of L-type calcium channel function [45]. Loss of APP leads to increased levels of the L-type calcium channel subunit Cav1.2 in the striatum, which is associated with reduced GABAergic paired pulse inhibition and increased GABAergic post-tetanic potentiation [45].…”

Section: App Aplp1 and Aplp2 Single Ko Micementioning

confidence: 99%

“…Recently, APP was found to be involved in the regulation of L-type calcium channel function [45]. Loss of APP leads to increased levels of the L-type calcium channel subunit Cav1.2 in the striatum, which is associated with reduced GABAergic paired pulse inhibition and increased GABAergic post-tetanic potentiation [45]. However, these behavioral and electrophysiological impairments may not be caused by a gross loss of neurons or synapses because unbiased stereological quantification failed to detect any significant neuronal or synapse loss in aged APP KO mice [42].…”

Section: App Aplp1 and Aplp2 Single Ko Micementioning

confidence: 99%

APP physiological and pathophysiological functions: insights from animal models

Guo

Wang

et al. 2011

Cell Res

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The amyloid precursor protein (APP) has been under intensive study in recent years, mainly due to its critical role in the pathogenesis of Alzheimer's disease (AD). β-Amyloid (Aβ) peptides generated from APP proteolytic cleavage can aggregate, leading to plaque formation in human AD brains. Point mutations of APP affecting Aβ production are found to be causal for hereditary early onset familial AD. It is very likely that elucidating the physiological properties of APP will greatly facilitate the understanding of its role in AD pathogenesis. A number of APP loss-and gainof-function models have been established in model organisms including Caenorhabditis elegans, Drosophila, zebrafish and mouse. These in vivo models provide us valuable insights into APP physiological functions. In addition, several knock-in mouse models expressing mutant APP at a physiological level are available to allow us to study AD pathogenesis without APP overexpression. This article will review the current physiological and pathophysiological animal models of APP.

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Amyloid Precursor Protein Regulates Ca_v1.2 L-type Calcium Channel Levels and Function to Influence GABAergic Short-Term Plasticity

Abstract: Amyloid precursor protein (APP) has been strongly implicated in the pathogenesis of Alzheimer's disease (AD). Although impaired synaptic function is believed to be an early and causative event in AD, how APP physiologically regulates synaptic properties remains poorly understood. Here,

Cited by 102 publications

References 53 publications

Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a

Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a

Physiological Functions of APP Family Proteins

APP physiological and pathophysiological functions: insights from animal models

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Amyloid Precursor Protein Regulates Cav1.2 L-type Calcium Channel Levels and Function to Influence GABAergic Short-Term Plasticity

Abstract: Amyloid precursor protein (APP) has been strongly implicated in the pathogenesis of Alzheimer's disease (AD). Although impaired synaptic function is believed to be an early and causative event in AD, how APP physiologically regulates synaptic properties remains poorly understood. Here,

Cited by 102 publications

References 53 publications

Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a

Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a

Physiological Functions of APP Family Proteins

APP physiological and pathophysiological functions: insights from animal models

Contact Info

Product

Resources

About

Amyloid Precursor Protein Regulates Ca_v1.2 L-type Calcium Channel Levels and Function to Influence GABAergic Short-Term Plasticity