APP Processing and Synaptic Function

Kamenetz, Flavio; Tomita, Taisuke; Hsieh, Helen; Seabrook, Guy R.; Borchelt, David R.; Iwatsubo, Takeshi; Sisodia, Sangram S.; Malinow, Roberto

doi:10.1016/s0896-6273(03)00124-7

Cited by 1,400 publications

(1,335 citation statements)

References 66 publications

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“…13,14 In healthy brain, non-amyloidogenic and amyloidogenic processing are balanced, with Ab peptides being important effectors in synaptic transmission and plasticity. 15,16 In 2003, Yang et al reported enhanced BACE1-mediated amyloidogenic cleavage in AD. 17 Recent evidence suggests that BACE1 activity can be elevated much earlier and may foster the conversion from mild cognitive impairment to AD.…”

Section: Role Of Bace1 In Admentioning

confidence: 99%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

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b-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.

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Section: Role Of Bace1 In Admentioning

confidence: 99%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

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“…Kamenetz and coworkers demonstrated that increased synaptic activity enhanced the formation and secretion of A β peptide in hippocampal slice neurons (Kamenetz et al , 2003 ). In turn, A β selectively depresses excitatory synaptic transmission onto neurons that overexpress APP as well as nearby neurons that do not.…”

Section: App Metabolism and A β Formationmentioning

confidence: 99%

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Bordji

Becerril-Ortega

2011

Revneuro

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A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β , contributing to the initiation of Alzheimer ' s disease. Among the different routes of Ca 2 + entry, N -methyld -aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca 2 + infl ux. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer ' s disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia.

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“…6,7 Release of the extracellular domain of APP from presynaptic terminals has been observed in response to electrical activity. 8 This domain, in turn, regulates neuronal excitability 1 and enhances proliferation of progenitor cells in the subventricular zone. 9 Not only is the intracellular domain of APP of functional importance, but the proteolytic fragments derived from the extracellular domain are also of interest.…”

Section: Introductionmentioning

confidence: 99%

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

et al. 2007

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Amyloid precursor protein (APP) and amyloid b-peptide (Ab) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit a as a binding partner of the extracellular domain of APP and Ab. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit a reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit a. The extracellular domain of APP and Ab partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Ab is similar in structure to the ATP synthase-binding sequence of the inhibitor of F1 (IF 1 ), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Ab and IF 1 similarly impair both short-and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Ab regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Ab-mediated Alzheimer's disease pathology.

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APP Processing and Synaptic Function

Cited by 1,400 publications

References 66 publications

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

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