Amyloid beta mediates memory formation

García‐Osta, Ana; Alberini, Cristina M.

doi:10.1101/lm.1310209

Cited by 151 publications

(122 citation statements)

References 55 publications

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“…Our laboratory and others have previously demonstrated that Aβ can have positive modulatory effects on synaptic plasticity and cognition at non-pathological, low picomolar concentrations [9–11]. Specifically, we demonstrated that both hippocampal long-term potentiation (LTP) and hippocampal-dependent learning and memory can be enhanced by the acute administration of 200 pM Aβ 42 [9].…”

Section: Introductionmentioning

confidence: 76%

Picomolar Amyloid-β Peptides Enhance Spontaneous Astrocyte Calcium Transients

Lee

Kosuri

Arancio

2013

JAD

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Amyloid-β (Aβ) peptides are constitutively produced in the brain throughout life via mechanisms that can be regulated by synaptic activity. Although Aβ has been extensively studied as the pathological plaque-forming protein species in Alzheimer’s disease (AD), little is known about the normal physiological function(s) and signaling pathway(s). We previously discovered that physiologically-relevant, low picomolar amounts of Aβ can enhance synaptic plasticity and hippocampal-dependent cognition in mice. In this study, we demonstrated that astrocytes are cellular candidates for participating in this type of Aβ signaling. Using calcium imaging of primary astrocyte cultures, we observed that picomolar amounts of Aβ peptides can enhance spontaneous intracellular calcium transient signaling. After application of 200 pM Aβ42 peptides, the frequency and amplitude averages of spontaneous cytosolic calcium transients were significantly increased. These effects were dependent on α7 nicotinic acetylcholine receptors (α7-nAChRs), as the enhancement effects were blocked by a pharmacological α7-nAChR inhibitor and in astrocytes from an α7 deficient mouse strain. We additionally examined evoked intercellular calcium wave signaling but did not detect significant picomolar Aβ-induced alterations in propagation parameters. Overall, these results indicate that at a physiologically-relevant low picomolar concentration, Aβ peptides can enhance spontaneous astrocyte calcium transient signaling via α7-nAChRs. Since astrocyte-mediated gliotransmission has been previously found to have neuromodulatory roles, Aβ peptides may have a normal physiological function in regulating neuron-glia signaling. Dysfunction of this signaling process may underlie glia-based aspects of AD pathogenesis.

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Section: Introductionmentioning

confidence: 76%

Picomolar Amyloid-β Peptides Enhance Spontaneous Astrocyte Calcium Transients

Lee

Kosuri

Arancio

2013

JAD

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“…This concentration range of A β was also measured in the ISF of mice subjected to a circadian rhythm, with more elevated levels when awake (Kang et al , 2009 ). Moreover, other authors reported that A β levels in the picomolar range enhanced synaptic plasticity and memory (Puzzo et al , 2008 ;Garcia -Osta and Alberini, 2009 ). Thus, these data support the idea that A β secretion could be a physiological event occurring with normal brain activity.…”

Section: App Metabolism and A β Formationmentioning

confidence: 90%

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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“…Interestingly, there have been prior rodent behavior studies that involve external delivery of Aβ 1-42 directly into the brain. 22,30 Taken together, these limitations need to be considered when designing in vivo mouse studies employing this model.…”

Section: Discussionmentioning

confidence: 99%

Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus

Jean

Baleriola

Fà

et al. 2015

JoVE

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Alzheimer's disease is a neurodegenerative disease affecting the aging population. A key neuropathological feature of the disease is the over-production of amyloid-beta and the deposition of amyloid-beta plaques in brain regions of the afflicted individuals. Throughout the years scientists have generated numerous Alzheimer's disease mouse models that attempt to replicate the amyloid-beta pathology. Unfortunately, the mouse models only selectively mimic the disease features. Neuronal death, a prominent effect in the brains of Alzheimer's disease patients, is noticeably lacking in these mice. Hence, we and others have employed a method of directly infusing soluble oligomeric species of amyloid-beta -forms of amyloid-beta that have been proven to be most toxic to neurons -stereotaxically into the brain. In this report we utilize male C57BL/6J mice to document this surgical technique of increasing amyloid-beta levels in a select brain region. The infusion target is the dentate gyrus of the hippocampus because this brain structure, along with the basal forebrain that is connected by the cholinergic circuit, represents one of the areas of degeneration in the disease. The results of elevating amyloid-beta in the dentate gyrus via stereotaxic infusion reveal increases in neuron loss in the dentate gyrus within 1 week, while there is a concomitant increase in cell death and cholinergic neuron loss in the vertical limb of the diagonal band of Broca of the basal forebrain. These effects are observed up to 2 weeks. Our data suggests that the current amyloid-beta infusion model provides an alternative mouse model to address region specific neuron death in a short-term basis. The advantage of this model is that amyloid-beta can be elevated in a spatial and temporal manner. Video LinkThe video component of this article can be found at

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Amyloid beta mediates memory formation

Cited by 151 publications

References 55 publications

Picomolar Amyloid-β Peptides Enhance Spontaneous Astrocyte Calcium Transients

Picomolar Amyloid-β Peptides Enhance Spontaneous Astrocyte Calcium Transients

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

Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus

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