Amyloid-β Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory

Palmeri, Agostino; Ricciarelli, Roberta; Gulisano, Walter; Rivera, Daniela; Rebosio, Claudia; Calcagno, E; Tropea, Maria Rosaria; Conti, Silvia; Das, Utpal; Roy, Subhojit; Pronzato, Maria Adelaide; Arancio, Ottavio; Fedele, Ernesto; Puzzo, Daniela

doi:10.1523/jneurosci.3607-16.2017

Cited by 65 publications

(45 citation statements)

References 59 publications

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“…Aβ is widely distributed through the body in AD patients and healthy individuals; there is evidence that soluble Aβ serves a variety of physiological functions in regulating neuronal electrophysiology, synaptic plasticity and memory, long‐term potentiation, neuronal transmission, learning and memory, hippocampal and memory consolidation, neurogenesis, and neuronal survival …”

Section: Physiological Role Of Aβmentioning

confidence: 99%

Amyloid‐β immunotherapy for alzheimer disease: Is it now a long shot?

Panza

Lozupone

Seripa

et al. 2019

Annals of Neurology

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Section: Physiological Role Of Aβmentioning

confidence: 99%

Amyloid‐β immunotherapy for alzheimer disease: Is it now a long shot?

Panza

Lozupone

Seripa

et al. 2019

Annals of Neurology

150

100

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“…All drugs were diluted in ACSF or saline solution (0.9% NaCl) to the desired final concentration right before electrophysiological or behavioral experiments. 6E10 (Covance, catalog #SIG-39320, RRID:AB_662798, 1:300) and M3.2 (Covance, catalog #SIG-39155, RRID:AB_2028758, 2 g/ml) antibodies used for electrophysiological experiments were directly diluted in ACSF according to previous studies (Ripoli et al, 2014;Palmeri et al, 2017).…”

Section: Drugsmentioning

confidence: 99%

“…The NOR test was performed as described previously (Bollen et al, 2014;Palmeri et al, 2017) in sex-balanced WT mice. Mice underwent 3 d of habituation to the arena, objects, and intrahippocampal injections; 1 d of training (T1); and 1 d of testing (T2).…”

Section: Novel Object Recognition (Nor) Testmentioning

confidence: 99%

“…Because LTP represents the cellular surrogate of memory, we assessed whether bilateral intrahippocampal injections with 200 pM oA␤ 42 20 min before training were able to convert STM into LTM. To this end, we used an NOR protocol in which the short time exposure (3 min) during the training phase (T1) does not allow animals to discriminate between the old and the new object after a 24 h long-term interval due to natural forgetting (Bollen et al, 2014;Palmeri et al, 2017). The analyses of the discrimination index indicated that mice receiving a weak stimulus (i.e., short exposure in T1) paired with 200 pM oA␤ 42 were able to discriminate between the old and the familiar object after 24 h compared with vehicle-treated animals showing natural forgetting.…”

Section: Picomolar Concentrations Of Oa␤ 42 Affect Ppf and Convert E-mentioning

confidence: 99%

“…In addition to its neuroprotective activity (Pearson and Peers, 2006), A␤ is likely to act as a neuromodulator at the synapse, where it is released during neuronal activity (Kamenetz et al, 2003;Brody et al, 2008) and is dynamically regulated by presynaptic mechanisms involving vesicle cycling (Cirrito et al, 2005(Cirrito et al, , 2008. Our previous studies have shown that A␤ production increases during the induction of long-term potentiation (LTP) (Palmeri et al, 2017) and contextual fear learning (Puzzo et al, 2011) and that blocking its function in the healthy brain impairs LTP and memory (Garcia-Osta and Alberini, 2009;Morley et al, 2010;Puzzo et al, 2011). Moreover, administration of picomolar concentrations of the peptide, mimicking its physiological content in the brain (Schmidt et al, 2005;Puzzo et al, 2008), enhances LTP and memory (Puzzo et al, 2008;Morley et al, 2010), suggesting that A␤ acts in a hormetic fashion exerting a biphasic effect depending upon its concentration (Puzzo et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory

et al. 2019

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Failure of anti-amyloid-␤ peptide (A␤) therapies against Alzheimer's disease (AD), a neurodegenerative disorder characterized by high amounts of the peptide in the brain, raised the question of the physiological role of A␤ released at low concentrations in the healthy brain. To address this question, we studied the presynaptic and postsynaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric A␤ 42 (oA␤ 42) on synaptic glutamatergic function in male and female mice. We found that 200 pM oA␤ 42 induces an increase of frequency of miniature EPSCs and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level. oA␤ 42 also produced postsynaptic changes as shown by an increased length of postsynaptic density, accompanied by an increased expression of plasticity-related proteins such as cAMPresponsive element binding protein phosphorylated at Ser133, calcium-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for A␤ in synaptic tagging. These changes resulted in the conversion of early into late long-term potentiation through the nitric oxide/cGMP/protein kinase G intracellular cascade consistent with a cGMP-dependent switch from short-to long-term memory observed in vivo after intrahippocampal administration of picomolar amounts of oA␤ 42. These effects were present upon extracellular but not intracellular application of the peptide and involved ␣7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oA␤ 42 in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high A␤ levels in the AD brains.

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Decreased Frontal Gamma Activity in Alzheimer Disease Patients

Casula

Pellicciari

Bonnı̀

et al. 2022

Annals of Neurology

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Objective In Alzheimer disease (AD) animal models, synaptic dysfunction has recently been linked to a disorder of high‐frequency neuronal activity. In patients, a clear relation between AD and oscillatory activity remains elusive. Here, we attempt to shed light on this relation by using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS‐EEG) to probe oscillatory activity in specific hubs of the frontoparietal network in a sample of 60 mild‐to‐moderate AD patients. Methods Sixty mild‐to‐moderate AD patients and 21 age‐matched healthy volunteers (HVs) underwent 3 TMS‐EEG sessions to assess cortical oscillations over the left dorsolateral prefrontal cortex, the precuneus, and the left posterior parietal cortex. To investigate the relations between oscillatory activity, cortical plasticity, and cognitive decline, AD patients underwent a TMS‐based neurophysiological characterization and a cognitive evaluation at baseline. The latter was repeated after 24 weeks to monitor clinical evolution. Results AD patients showed a significant reduction of frontal gamma activity as compared to age‐matched HVs. In addition, AD patients with a more prominent decrease of frontal gamma activity showed a stronger impairment of long‐term potentiation–like plasticity and a more pronounced cognitive decline at subsequent follow‐up evaluation at 24 weeks. Interpretation Our data provide novel evidence that frontal lobe gamma activity is dampened in AD patients. The current results point to the TMS‐EEG approach as a promising technique to measure individual frontal gamma activity in patients with AD. This index could represent a useful biomarker to predict disease progression and to evaluate response to novel pharmacological therapies. ANN NEUROL 2022;92:464–475

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Amyloid-β Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory

Cited by 65 publications

References 59 publications

Amyloid‐β immunotherapy for alzheimer disease: Is it now a long shot?

Amyloid‐β immunotherapy for alzheimer disease: Is it now a long shot?

Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory

Decreased Frontal Gamma Activity in Alzheimer Disease Patients

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