Impairments of long-term potentiation in hippocampal slices of β-amyloid-infused rats

Itoh, Akio; Akaike, Tadashi; Sokabe, Masahiro; Nitta, Atsumi; Iida, Ryo; Olariu, Ana; Yamada, Kiyofumi; Nabeshima, Toshitaka

doi:10.1016/s0014-2999(99)00601-9

Cited by 113 publications

(67 citation statements)

References 53 publications

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“…To test this possibility, we studied LTP responses in acute mouse hippocampal slices. As expected from previous reports (18,19) we found that A␤ strongly inhibited LTP generation in the CA1 hippocampal region when slices were exposed to 200 nM A␤ for 20 min before tetanic stimulation of the Schaeffer collateral pathway (137.54 Ϯ 6.14% of baseline slope at 60 min after tetanus, n ϭ 9; Fig. 4A).…”

Section: Resultssupporting

confidence: 90%

See 1 more Smart Citation

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Vitolo

Sant’Angelo

Costanzo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

496

422

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Changes in hippocampal function seem critical for cognitive impairment in Alzheimer's disease (AD). Although there is eventual loss of synapses in both AD and animal models of AD, deficits in spatial memory and inhibition of long-term potentiation (LTP) precede morphological alterations in the models, suggesting earlier biochemical changes in the disease. In the studies reported here we demonstrate that amyloid ␤-peptide (A␤) treatment of cultured hippocampal neurons leads to the inactivation of protein kinase A (PKA) and persistence of its regulatory subunit PKAII␣. Consistent with this, CREB phosphorylation in response to glutamate is decreased, and the decrease is reversed by rolipram, a phosphodiesterase inhibitor that raises cAMP and leads to the dissociation of the PKA catalytic and regulatory subunits. It is likely that a similar mechanism underlies 〈␤ inhibition of LTP, because rolipram and forskolin, agents that enhance the cAMP-signaling pathway, can reverse this inhibition. This reversal is blocked by H89, an inhibitor of PKA. These observations suggest that 〈␤ acts directly on the pathways involved in the formation of late LTP and agents that enhance the cAMP͞PKA͞CREB-signaling pathway have potential for the treatment of AD. A lzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by mild cognitive impairment at its onset and deficits in multiple cortical functions in later stages. To date, the vast majority of its symptoms have been attributed to the loss of synapses and the death of neurons that occur in the course of the disease. The overproduction and accumulation of the amyloid ␤-peptide (A␤) and particularly its 42-aa form (A␤ 1-42 ) have been shown to play a crucial role in both of these processes in animal models of AD (1, 2). Although these phenomena can account for the late debilitating stages of the disease, the mechanisms by which A␤ causes early cognitive and behavioral changes remain a matter of conjecture. Recent studies on animal models of AD have highlighted the discrepancy between behavioral deficits and neuropathological findings. Electrophysiological studies on mice that overexpress A␤ show impairment of long-term potentiation (LTP) that does not correlate with the extent of synaptic loss, amyloid deposition, or cell death (3-5). In addition, animals without detectable accumulation of A␤ have been reported to have behavioral deficits (6, 7). While examining gene expression in nerve growth factorprimed PC12 cells that had been exposed to A␤ 1-42 for 3 h, we observed that a group of genes including CREB2 (ATF4) and ubiquitin C-terminal hydrolase, which have been implicated in the switch from early to late LTP, were regulated in a manner consistent with an 〈␤-mediated inhibition of the cAMPmediated signaling pathway for the consolidation of LTP. ʈ The details of the biochemical pathway mediating the switch from early to late LTP have been worked out in aplysia and mice (8) and depend on the activation of the transcription factor CREB by phosphorylat...

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Section: Resultssupporting

confidence: 90%

“…These results strongly suggest that inhibition of the PKA͞ CREB pathway underlies the effects of A␤ on LTP (18,19) and that drugs that enhance PKA activity might be able to reverse this inhibition in the brain. To test this possibility, we studied LTP responses in acute mouse hippocampal slices.…”

Section: Resultsmentioning

confidence: 80%

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Vitolo

Sant’Angelo

Costanzo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

496

422

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“…However one study reported that LTP in CA1 was decreased in hippocampal slices obtained from rats which received A 1-40 for 10-11 days (Itoh et al, 1999) while others reported that hippocampal-dependent learning is depressed in rats treated chronically with A 1-40 or A 1-40 +A 1-42 (Frautschy et al, 2001;Nitta et al, 1997) and the findings of the present study are consistent with this. Here we coupled the A -induced inhibition of LTP with increased activity of caspase 3 in hippocampus; this is indicative of cell stress, although not necessarily cell death (Garnier et al, 2004), and consistent with several reports which show that A increases cell stress in vivo and in vitro (Boland and Campbell, 2004;Clarke et al, 2007;Lyons et al, 2007).…”

Section: Discussionsupporting

confidence: 90%

The deficit in long-term potentiation induced by chronic administration of amyloid-β is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025

Miller

Piazza

Martin

et al. 2009

Experimental Gerontology

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, et al.. The deficit in long-term potentiation induced by chronic administration of amyloid-β-is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025. Experimental Gerontology, Elsevier, 2009, 44 (4), pp.300. <10.1016/j.exger.2008.12.001>. Accepted ManuscriptThe deficit in long-term potentiation induced by chronic administration of amyloid-β-is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025 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 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. ACCEPTED MANUSCRIPTThe deficit in long-term potentiation induced by chronic administration of amyloid--is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025 ACCEPTED MANUSCRIPT ABSTRACTAmyloid-(A ) peptides, the primary component of the amyloid plaques in Alzheimer's disease (AD), exert profound effects on neurons in vitro and negatively impact on neuronal function in vivo. One of the consequences of increased A in the brain, either as a result of overexpression of the precursor amyloid precursor protein in transgenic mice, or injection into the brain is a decrease in one form of synaptic plasticity, long-term potentiation (LTP) in the hippocampus. Here we investigated the effect of infusion of A for 28 days on LTP in dentate gyrus of rats and demonstrate that it was profoundly decreased compared with control-treated rats. We show that this effect is accompanied by increased activity of caspase 3, which is an indicator of cell stress. Significantly these changes were attenuated in animals which were pretreated with particles incorporating phosphatidylglycerol (VP025) and the evidence indicated that even when treatment was given 2 weeks after the start of the A infusion, VP025 was capable of attenuating A -induced changes. The evidence suggests that activation of caspase 3 was mediated by an A -induced increase in sphingomyelinase, with the subsequent production of ceramide which is known to have a detrimental effect on neuronal function.

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“…A prominent form of synaptic plasticity is long-term potentiation (LTP), a sustained increase in excitatory synaptic transmission. Certain species of synthetic A␤, especially A␤ , acutely inhibit the induction of LTP in the hippocampus without affecting basal synaptic transmission (Cullen et al, 1997;Lambert et al, 1998;Itoh et al, 1999;Chen et al, 2000;Stephan et al, 2001;Vitolo et al, 2002). In a recent study, we showed that LTP induction in the hippocampus in vivo was inhibited by a cell medium containing naturally secreted human A␤ oligomers but not monomers or fibrils (Walsh et al, 2002).…”

Section: Introductionmentioning

confidence: 97%

Block of Long-Term Potentiation by Naturally Secreted and Synthetic Amyloid β-Peptide in Hippocampal Slices Is Mediated via Activation of the Kinases c-Jun N-Terminal Kinase, Cyclin-Dependent Kinase 5, and p38 Mitogen-Activated Protein Kinase as well as Metabotropic Glutamate Receptor Type 5

Wang¹,

Walsh²,

Rowan³

et al. 2004

J. Neurosci.

422

346

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Impairments of long-term potentiation in hippocampal slices of β-amyloid-infused rats

Cited by 113 publications

References 53 publications

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

The deficit in long-term potentiation induced by chronic administration of amyloid-β is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025

Block of Long-Term Potentiation by Naturally Secreted and Synthetic Amyloid β-Peptide in Hippocampal Slices Is Mediated via Activation of the Kinases c-Jun N-Terminal Kinase, Cyclin-Dependent Kinase 5, and p38 Mitogen-Activated Protein Kinase as well as Metabotropic Glutamate Receptor Type 5

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