Figure 3 - uploaded by Ana García-Osta
Content may be subject to copyright.
The nicotinic receptor antagonist mecamylamine (MCA) mimics the effect of the antiAb(1-42) antibody. Memory acquisition (Acq) and retention expressed as mean latency 6 SEM (in seconds, s) of rats that received intrahippocampal injections of saline or MCA 15 min before IA training (A) or immediately after IA training (B). STM was tested 1 h after training and LTM was tested 24 h after training. ** P < 0.01, *** P < 0.001. (C) Effect of intrahippocampal injection of saline or MCA on nociceptive hot plate test. Rats injected with MCA or saline underwent the hot plate test 15 min after injection (Carter 1991). Values are the mean 6 SEM of response latencies measured in seconds. No difference in hot plate latencies was detected between the two groups. (D) Effect of intrahippocampal injection of saline or MCA on locomotor activity. One hour after injection of either saline or MCA rats were tested for locomotor activity as described in Figure 1. Values are the mean 6 SEM of motility counts. No difference in locomotor activity was detected between the two groups.
Source publication
The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid beta (1-42) peptide (Abeta[1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated, endogeno...
Contexts in source publication
Context 1
... was tested 1 h after training and LTM was tested 24 h after train- ing. Only the pre-training bilateral injections produced a signifi- cant memory impairment at both short-(veh: 298.8 6 59.9 sec; MCA: 86.1 6 26.3 sec, n = 8 per group, P < 0.01) and long-term time points (veh: 385.0 6 61.8 sec; MCA: 25.2 6 4.6 sec, n = 8 per group, P < 0.001; Fig. 3A), whereas post-training administration had no effect on either short-(veh: 217.5 6 59.2 sec; MCA: 280.6 6 67.4 sec, n = 8 per group) or long-term retentions (veh: 345.8 6 84.7 sec; MCA: 312.2 6 67.7 sec, n = 8 per group; Fig. 3B). Neither locomotor activity nor nociceptive sensitivity was affected by MCA treatment (Fig. 3C,D; n = 5 per ...
Context 2
... per group, P < 0.01) and long-term time points (veh: 385.0 6 61.8 sec; MCA: 25.2 6 4.6 sec, n = 8 per group, P < 0.001; Fig. 3A), whereas post-training administration had no effect on either short-(veh: 217.5 6 59.2 sec; MCA: 280.6 6 67.4 sec, n = 8 per group) or long-term retentions (veh: 345.8 6 84.7 sec; MCA: 312.2 6 67.7 sec, n = 8 per group; Fig. 3B). Neither locomotor activity nor nociceptive sensitivity was affected by MCA treatment (Fig. 3C,D; n = 5 per group), excluding that the memory impairments obtained with this treatment were due to nonspecific ...
Context 3
... 8 per group, P < 0.001; Fig. 3A), whereas post-training administration had no effect on either short-(veh: 217.5 6 59.2 sec; MCA: 280.6 6 67.4 sec, n = 8 per group) or long-term retentions (veh: 345.8 6 84.7 sec; MCA: 312.2 6 67.7 sec, n = 8 per group; Fig. 3B). Neither locomotor activity nor nociceptive sensitivity was affected by MCA treatment (Fig. 3C,D; n = 5 per group), excluding that the memory impairments obtained with this treatment were due to nonspecific ...
Similar publications
Effect of administration of the standardized extract of Ginkgo biloba leaves (EGb 761) on learning, memory and exploratory behavior was estimated in water maze and hole-board tests. Rats (18-month old) received for three months EGb 761 at doses: 50, 100 and 150 mg/kg b.w. per day. After completion of the behavioral experiment, concentrations of neu...
Memory consolidation is a process to stabilize short-term memory, generating long-term memory. A critical biochemical feature of memory consolidation is a requirement for gene expression. Previous studies have shown that fear memories are consolidated through the activation of gene expression in the amygdala and hippocampus, indicating essential ro...
Rats must forage adaptively, choose safe foods, and avoid poisonous foods. The social transmission of food preference paradigm is useful to study learning and memory. Several studies have found that the associations formed in that paradigms are examples of declarative memory. Scopolamine induces interference in learning and consolidation of memorie...
DROULERS O. & ROULLET B., Does Crime Pay for Violent Program-Embedded Ads? , in B.E. Kahn & M.F. Luce (eds.), Advances in Consumer Research, vol. 31, 2004, ACR North American Conference, 8-12 October 2003, Toronto, Ontario. Abstract : This paper aims at studying the impact of emotional context in television programs on ad memorization. Many experim...
A recently reported phenomenon, termed attribute amnesia, challenged the commonly held belief that attention plays the determining role in controlling how information is remembered, by showing that participants fail to remember a specific attended attribute (e.g., the target-defining color), even when they had just used that attribute to perform a...
Citations
... One of the most striking findings is the physiological role of the amyloid peptide in memory, which started to emerge in the mid 1990s, when exogenous Aβ was shown to enhance hippocampal long-term potentiation (LTP), the synaptic plasticity phenomenon representing the electrophysiological correlate of memory formation/consolidation [147]. This observation was confirmed and extended by several studies demonstrating that low concentrations of exogenous Aβ enhanced hippocampal LTP and improved hippocampaldependent memory (both effects mediated by α7-nicotinic receptors), whereas its immunomediated depletion abrogated LTP and induced significant cognitive impairments, which were rescued by physiological concentrations of the amyloid peptide [148][149][150][151]. In addition, it was found that physiological Aβ production is enhanced by both cAMP and cGMP, although through different mechanisms, and that the peptide is necessary for both nucleotides to trigger LTP and memory formation [152][153][154][155]. Indirect evidence of Aβ involvement in memory was also provided by studies showing that BACE1 knocking out or its pharmacological inhibition caused LTP alterations and cognitive deficits in mice [156,157]. ...
Over the past 30 years, the majority of (pre)clinical efforts to find an effective therapy for Alzheimer’s disease (AD) focused on clearing the β-amyloid peptide (Aβ) from the brain since, according to the amyloid cascade hypothesis, the peptide was (and it is still considered by many) the pathogenic determinant of this neurodegenerative disorder. However, as reviewed in this article, results from the numerous clinical trials that have tested anti-Aβ therapies to date indicate that this peptide plays a minor role in the pathogenesis of AD. Indeed, even Aducanumab and Lecanemab, the two antibodies recently approved by the FDA for AD therapy, as well as Donanemab showed limited efficacy on cognitive parameters in phase III clinical trials, despite their capability of markedly lowering Aβ brain load. Furthermore, preclinical evidence demonstrates that Aβ possesses several physiological functions, including memory formation, suggesting that AD may in part be due to a loss of function of this peptide. Finally, it is generally accepted that AD could be the result of many molecular dysfunctions, and therefore, if we keep chasing only Aβ, it means that we cannot see the forest for the trees.
... 371,372 In contrast, removal of endogenous Aβ by injection of anti-Aβ antibodies or genetic manipulation greatly decreased LTP and impaired memory, which could be rescued by the addition of human Aβ 42 . 357,[373][374][375][376] Together, the possible role of Aβ peptide in the modulation of synaptic function as well as learning and memory has been suggested. Aβ monomers stimulated astrocytes to increase the clearance of synaptic glutamate and therefore protect neurons from glutamate excitotoxicity. ...
Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer's disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer's pathogenesis and progression. Aβ has been the prime target for the development of AD therapy. However, the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer's drug has followed the correct course. However, the recent successes of Aβ targeted trials have assuaged those doubts. In this review, we discussed the evolution of the amyloid cascade hypothesis over the last 30 years and summarized its application in Alzheimer's diagnosis and modification. In particular, we extensively discussed the pitfalls, promises and important unanswered questions regarding the current anti-Aβ therapy, as well as strategies for further study and development of more feasible Aβ-targeted approaches in the optimization of AD prevention and treatment.
... In short, studies by several labs have found that at low concentrations and likely as monomers and/or low-molecular-weight oligomers, Aβ increases presynaptic vesicle pool, vesicle release probability, and as a result miniature EPSC frequency [15][16][17]. It also enhances long-term potentiation (LTP) in brain slices and several forms of learning and memory in vivo [17][18][19][20][21][22]. Indeed, recent studies show Aβ monomers may in fact be synaptogenic [23]. ...
... Besides homeostatic plasticity, other forms of plasticity are also regulated by cytokines such as IL-1β and IL-6 [165][166][167][168]. In addition, antibody blocking studies have implicated a role of endogenous Aβ in hippocampal LTP as well as learning and memory [20,21,169]. Thus, these results strongly suggest that the Aβ/cytokine signaling module that regulates axonal competition during development may be conserved and regulate homeostatic synaptic plasticity in the adult brain. ...
Amyloid-β protein precursor (AβPP) gives rise to amyloid-β (Aβ), a peptide at the center of Alzheimer’s disease (AD). AβPP, however, is also an ancient molecule dating back in evolution to some of the earliest forms of metazoans. This suggests a possible ancestral function that may have been obscured by those that evolve later. Based on literature from the functions of Aβ/AβPP in nervous system development, plasticity, and disease, to those of anti-microbial peptides (AMPs) in bacterial competition as well as mechanisms of cell competition uncovered first by Drosophila genetics, I propose that Aβ/AβPP may be part of an ancient mechanism employed in cell competition, which is subsequently co-opted during evolution for the regulation of activity-dependent neural circuit development and plasticity. This hypothesis is supported by foremost the high similarities of Aβ to AMPs, both of which possess unique, opposite (i.e., trophic versus toxic) activities as monomers and oligomers. A large body of data further suggests that the different Aβ oligomeric isoforms may serve as the protective and punishment signals long predicted to mediate activity-dependent axonal/synaptic competition in the developing nervous system and that the imbalance in their opposite regulation of innate immune and glial cells in the brain may ultimately underpin AD pathogenesis. This hypothesis can not only explain the diverse roles observed of Aβ and AβPP family molecules, but also provide a conceptual framework that can unify current hypotheses on AD. Furthermore, it may explain major clinical observations not accounted for and identify approaches for overcoming shortfalls in AD animal modeling.
... Tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrroloisoxazole analogs have been developed and studied for treatment of AD. The approved drugs like rivastigmine, donepezil, and galantamine promote higher Ach levels and improves the brains cholinergic function by inhibiting acetylcholinesterase which degrades the neurotransmitter (5,15) . However, these have the history of showing adverse effects related to sleep disturbances, cardiorespiratory, gastrointestinal, genitourinary and musculoskeletal symptoms. ...
Alzheimer's Disease is a neurodegenerative disorder which is detected approximately after 20 years of incidence and to the death of the individual. It is noted that by 2050 the incidence of the disease will be three times more when compared to present conditions. 70% of the individuals are facing the challenge of AD in western countries. Current treatments available are acetylcholinesterase inhibitors and NMDA antagonists that show adverse effects such as musculoskeletal symptoms, cardiorespiratory, sleep disturbances, gastrointestinal, extrapyramidal, drug-drug interactions with cholinergic inhibitors and low affinity rates with selective NMDA antagonists. To overcome the situation of late detection and to avoid the adverse effects of current treatments biomarkers serves as a major source. Aβ and Tau are serving as the AD biomarkers. These are initially detected in blood samples and many other tests such as CT scans, PET scans, Genetic testing etc., However, these blood tests are not being the final source of AD detection as they do not specifically target. In this article we focussed on current treatments available for AD, types of biomarkers, biomarker tests that are initially done to detect AD. Though there are many blood tests and scans available right now for the detection of the disease. The results that are being shown by the tests are not appropriate and need more development in the tests and biomarker detection. Many researches should be conducted to overcome this issue. Future of biomarkers: help to identify and solve the issues in the treatment concerns and early detection of the disease to improve the quality of life. By increasing the availability of the treatment up to 85%.
... At the synapse, Aβ is secreted in an activity-dependent fashion dynamically regulated by vesicle cycling [46][47][48][49], and its production increases during LTP and memory [50,51]. Indeed, endogenous Aβ is needed for memory formation since blocking its production and/or function results in an impairment of LTP and memory [50,52,53]. Several studies have demonstrated that, in physiological concentrations, Aβ acting through α7 nicotinic acetylcholine receptors (α7nAChRs) activated the Mitogen-Activated Protein Kinase Cascade [54,55], regulated recycling of synaptic vesicles [56], modulated glutamate, aspartate, GABA, glycine, and dopamine release [57][58][59][60][61], enhanced neurotransmitter release, frequency of miniature excitatory post-synaptic currents, docked vesicle number, length of postsynaptic density, and the expression of plasticity-related proteins such as phospho-CREB (p-CREB), calcium-calmodulin-dependent kinase II and BDNF [62]. ...
The nitric oxide (NO)/cGMP pathway has been extensively studied for its pivotal role in synaptic plasticity and memory processes, resulting in an increase of cAMP response element-binding (CREB) phosphorylation, and consequent synthesis of plasticity-related proteins. The NO/cGMP/CREB signaling is downregulated during aging and neurodegenerative disorders and is affected by Amyloid-β peptide (Aβ) and tau protein, whose increase and deposition is considered the key pathogenic event of Alzheimer's disease (AD). On the other hand, in physiological conditions, the crosstalk between the NO/cGMP/PKG/CREB pathway and Aβ ensures long-term potentiation and memory formation.
This review summarizes the current knowledge on the interaction between the NO/cGMP/PKG/CREB pathway and Aβ in the healthy and diseased brain, offering a new perspective to shed light on AD pathophysiology. We will focus on the synaptic mechanisms underlying Aβ physiological interplay with cGMP pathway and how this balance is corrupted in AD, as high levels of Aβ interfere with NO production and cGMP molecular signaling leading to cognitive impairment.
Finally, we will discuss results from preclinical and clinical studies proposing the increase of cGMP signaling as a therapeutic strategy in the treatment of AD.
... In such cases, markers, such as amyloid-β (Aβ) peptides and tau proteins, seem to be responsible for the loss of neurons at the hippocampus, basal forebrain, and other cortical areas [1,2]. Aβ peptides derive from enzyme proteolysis of the amyloid precursor protein (APP), and play physiological roles in memory formation and lipid homeostasis, regulation of neuronal activity, and neurite growth [3]. AD is characterized by an excessive accumulation of amyloid-β and neurofibrillary tangles, leading to neuronal damage due to interrelated pathological processes [1,2]. ...
Extracellular plaques composed of the hydrophobic peptide amyloid-β and intraneuronal accumulation of the hyperphosphorylated protein tau (p-tau) are pathological hallmarks found in the brains of most people affected by Alzheimer’s disease (AD). In Parkinson’s disease (PD), Lewy bodies, i.e., intraneuronal protein deposits comprising the protein α-synuclein, are a typical disease feature. As these hallmarks located in the brain are hardly traceable, reliable biomarkers from easily accessible body fluids are key for accurate diagnosis. The aim of the present work was to review the available literature regarding potential biomarkers of AD and PD in the saliva. The databases PubMed, Google Scholar, LILACS, LIVIVO, VHL regional portal, Cochrane Library, eLIBRARY, and IOS Press were consulted for the literature search. Screening of titles and abstracts followed the PRISMA guidelines, while data extraction and the assessment of full texts were carried out in accordance with the Newcastle–Ottawa Scale assessment. The review shows significant increases in levels of the amyloid-β Aβ1-42 and elevated p-tau to total tau (t-tau) ratios in salivary samples of AD patients, in comparison with healthy controls. In PD patients, levels of α-synuclein in salivary samples significantly decreased compared to healthy controls, whereas oligomeric α-synuclein and the ratio of oligomeric α-synuclein to total α-synuclein markedly increased. Salivary biomarkers represent a promising diagnostic tool for neurodegenerative diseases. Further high-quality case–control studies are needed to substantiate their accuracy.
... Furthermore, various methods, such as antibodies that specifically block Aβ, knockout (KO) mice model of Aβ and its related substrates, and Aβ injection, have been implemented to actively identify the potential role of Aβ peptides involved in synaptic functions, instead of simply observing the correlation between Aβ and synaptic activity. Starting with anti-Aβ antibodies, 4G8, DAKO, and HJ5.1 were separately injected to the hippocampi of rats and mice, and a significant performance decline in behavioral tests was observed compared to controls [50,51]. LTP, a type of neuronal activity associated with memory [52], was shown to be impaired when the endogenous Aβ was suppressed with antirodent JRF/rAb2 antibody [53]. ...
... However, given that the normal physiological level of Aβ peptides has been estimated to be in picomolar concentrations [64][65][66][67], the nanomolar concentrations of Aβ administered in the study largely deviates from the endogenous level of Aβ. To address this issue, other research groups attempted to inject picomolar concentrations of Aβ, and the injected mice performed better in behavioral tests as well, confirming the enhancing effect of Aβ on synaptic plasticity and memory formation [50,68]. ...
Alzheimer's disease (AD) progressively inflicts impairment of synaptic functions with notable deposition of amyloid-β (Aβ) as senile plaques within the extracellular space of the brain. Accordingly, therapeutic directions for AD have focused on clearing Aβ plaques or preventing amyloidogenesis based on the amyloid cascade hypothesis. However, the emerging evidence suggests that Aβ serves biological roles, which include suppressing microbial infections, regulating synaptic plasticity, promoting recovery after brain injury, sealing leaks in the blood-brain barrier, and possibly inhibiting the proliferation of cancer cells. More importantly, these functions were found in in vitro and in vivo investigations in a hormetic manner, that is to be neuroprotective at low concentrations and pathological at high concentrations. We herein summarize the physiological roles of monomeric Aβ and current Aβ-directed therapies in clinical trials. Based on the evidence, we propose that novel therapeutics targeting Aβ should selectively target Aβ in neurotoxic forms such as oligomers while retaining monomeric Aβ in order to preserve the physiological functions of Aβ monomers.
... Secretases, including β and γ-secretases, which are involved in the proteolytic generation of Aβ from amyloid precursor protein, have long been studied for their ability to inhibit the overproduction of Aβ and develop a number of substances, however, most of them failed in clinical trials [31,32]. This may be because these secretase inhibitors reduced endogenous Aβ monomers, which are known to have beneficial effects on brain functions, or because these secretases have physiological effects other than Aβ production [33][34][35][36][37]. Therefore, secretase inhibitors may block physiological events, resulting in detrimental side effects [31]. ...
Alzheimer’s disease (AD) is caused by various pathological mechanisms; therefore, it is necessary to develop drugs that simultaneously act on multiple targets. In this study, we investigated the effects of eugenitol, which has anti-amyloid β (Aβ) and anti-neuroinflammatory effects, in an AD mouse model. We found that eugenitol potently inhibited Aβ plaque and oligomer formation. Moreover, eugenitol dissociated the preformed Aβ plaques and reduced Aβ-induced nero2a cell death. An in silico docking simulation study showed that eugenitol may interact with Aβ1–42 monomers and fibrils. Eugenitol showed radical scavenging effects and potently reduced the release of proinflammatory cytokines from lipopolysaccharide-treated BV2 cells. Systemic administration of eugenitol blocked Aβ aggregate-induced memory impairment in the Morris water maze test in a dose-dependent manner. In 5XFAD mice, prolonged administration of eugenitol ameliorated memory and hippocampal long-term potentiation impairment. Moreover, eugenitol significantly reduced Aβ deposits and neuroinflammation in the hippocampus of 5XFAD mice. These results suggest that eugenitol, which has anti-Aβ aggregation, Aβ fibril dissociation, and anti-inflammatory effects, potently modulates AD-like pathologies in 5XFAD mice, and could be a promising candidate for AD therapy.
... In the context of AD, it is known that Aβ peptides are generated after the cleavage of APP by γ-secretase in the amyloidogenic pathway [10]. In previous models, the physiological concentration of Aβ peptides in the brain revealed a positive effect on neuroplasticity and learning, showing improved hippocampal long-term potentiation (LTP), while high nanomolar Aβ administration resulted in impaired cognition [49,50], suggesting a hormetic nature [51]. Because low picomolar levels of extracellular concentrations of Aβ in the normal brain have been estimated, in our experiments we chose a concentration of Aβ peptide 1-42 in the nanomolar range (50 nM), added once a week during the 29 days of culture, a single dose determined by the average of concentrations used by Gulisano et al. [52] and Malmsten et al. [53]. ...
In view of the proven link between adult hippocampal neurogenesis (AHN) and learning and memory impairment, we generated a straightforward adult neurogenesis in vitro model to recapitulate DNA methylation marks in the context of Alzheimer’s disease (AD). Neural progenitor cells (NPCs) were differentiated for 29 days and Aβ peptide 1–42 was added. mRNA expression of Neuronal Differentiation 1 (NEUROD1), Neural Cell Adhesion Molecule 1 (NCAM1), Tubulin Beta 3 Class III (TUBB3), RNA Binding Fox-1 Homolog 3 (RBFOX3), Calbindin 1 (CALB1), and Glial Fibrillary Acidic Protein (GFAP) was determined by RT-qPCR to characterize the culture and framed within the multistep process of AHN. Hippocampal DNA methylation marks previously identified in Contactin-Associated Protein 1 (CNTNAP1), SEPT5-GP1BB Readthrough (SEPT5-GP1BB), T-Box Transcription Factor 5 (TBX5), and Nucleoredoxin (NXN) genes were profiled by bisulfite pyrosequencing or bisulfite cloning sequencing; mRNA expression was also measured. NXN outlined a peak of DNA methylation overlapping type 3 neuroblasts. Aβ-treated NPCs showed transient decreases of mRNA expression for SEPT5-GP1BB and NXN on day 9 or 19 and an increase in DNA methylation on day 29 for NXN. NXN and SEPT5-GP1BB may reflect alterations detected in the brain of AD human patients, broadening our understanding of this disease.
... Thus, researchers have started to examine the role of Aβ beyond AD pathogenesis by looking into the endogenous Aβ characteristics and its role in memory formation . It has been observed that at low picomolar concentrations, Aβ enhances synaptic plasticity and memory consolidation process in hippocampal region (Garcia-Osta and Alberini, 2009;Wu et al., 1995). Similar observations have been reported in the study of Puzzo et al. (2011), in which it was observed that infusion of Aβ antibody attenuated the LTP and fear memory in rodents, whereas, the reduced memory was rescued by human Aβ 1-42 . ...
... Thus, it was concluded that endogenous Aβ is essential for the process of memory consolidation and enhancement of synaptic plasticity (Puzzo et al., 2011). It has been hypothesized that endogenous Aβ works closely with the nicotinic acetylcholine receptors and regulates the synaptic vesicle release of the neurotransmitters, thus making Aβ a crucial peptide for the maintenance of synaptic strength and memory consolidation process (Abramov et al., 2009;Garcia-Osta and Alberini, 2009;Puzzo et al., 2011). ...
Age-related cognitive decline is the major cause of concern due to its 70% more incidence than dementia cases worldwide. Moreover, aging is also the major risk factor of Alzheimer's disease (AD), associated with progressive memory loss. Approx. 13 million people will have Alzheimer-related memory decline by 2050. Learning and memory is the fundamental process of brain functions. However, the mechanism for the same is still under investigation. Thus, it is critical to understand the process of memory consolidation in the brain and extrapolate its understanding to the memory decline mechanism. Research on learning and memory has identified several molecular signatures such as Protein kinase M zeta (PKMζ), Calcium/calmodulin-dependent protein kinase II (CaMKII), Brain-derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB), Activity-regulated cytoskeleton-associated protein (Arc) crucial for the maintenance and stabilization of long-term memory in the brain. Interestingly, memory decline in AD has also been linked to the abnormality in expressing these memory-related molecular signatures. Hence, in the present consolidated review, we explored the role of these memory-related molecular signatures in long-term memory consolidation. Additionally, the effect of amyloid-beta toxicity on these molecular signatures is discussed in detail.
