Early Synaptic Dysfunction Research Articles

Specific Soluble Oligomers of Amyloid-β Peptide Undergo Replication and Form Non-fibrillar Aggregates in Interfacial Environments

Aggregates of amyloid-β (Aβ) peptides have been implicated in the etiology of Alzheimer disease. Among the different forms of Aβ aggregates, low molecular weight species ranging between ~2- and 50-mers, also called "soluble oligomers," have emerged as the species responsible for early synaptic dysfunction and neuronal loss. Emerging evidence suggests that the neurotoxic oligomers need not be formed along the obligatory nucleation-dependant fibril formation pathway. In our earlier work, we reported the isolation of one such "off-pathway" 12-18-mer species of Aβ42 generated from fatty acids called large fatty acid-derived oligomers (LFAOs) (Kumar, A., Bullard, R. L., Patel, P., Paslay, L. C., Singh, D., Bienkiewicz, E. A., Morgan, S. E., and Rangachari, V. (2011) PLoS One 6, e18759). Here, we report the physiochemical aspects of LFAO-monomer interactions as well as LFAO-LFAO associations in the presence of interfaces. We discovered that LFAOs are a replicating strain of oligomers that recruit Aβ42 monomers and quantitatively convert them into LFAO assemblies at the expense of fibrils, a mechanism similar to prion propagation. We also found that in the presence of hexane-buffer or chloroform-buffer interfaces LFAOs are able to associate with themselves to form larger but non-fibrillar aggregates. These results further support the hypothesis that low molecular weight oligomers can be generated via non-fibril formation pathways. Furthermore, the unique replicating property of off-pathway oligomers may hold profound significance for Alzheimer disease pathology.

Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington's disease

Synapse abnormalities in Huntington's disease (HD) patients can precede clinical diagnosis and neuron loss by decades. The polyglutamine expansion in the huntingtin (htt) protein that underlies this disorder leads to perturbations in many cellular pathways, including the disruption of Rab11-dependent endosomal recycling. Impairment of the small GTPase Rab11 leads to the defective formation of vesicles in HD models and may thus contribute to the early stages of the synaptic dysfunction in this disorder. Here, we employ transgenic Drosophila melanogaster models of HD to investigate anomalies at the synapse and the role of Rab11 in this pathology. We find that the expression of mutant htt in the larval neuromuscular junction decreases the presynaptic vesicle size, reduces quantal amplitudes and evoked synaptic transmission and alters larval crawling behaviour. Furthermore, these indicators of early synaptic dysfunction are reversed by the overexpression of Rab11. This work highlights a potential novel HD therapeutic strategy for early intervention, prior to neuronal loss and clinical manifestation of disease.

Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease.

The microtubule-associated protein Tau (MAPT) is a major component of the pathogenesis of a wide variety of brain-damaging disorders, known as tauopathies. These include Alzheimer's disease (AD), denoted as secondary tauopathy because of the obligatory combination with amyloid pathology. In all tauopathies, protein Tau becomes aberrantly phosphorylated, adopts abnormal conformations, and aggregates into fibrils that eventually accumulate as threads in neuropil and as tangles in soma. The argyrophilic neurofibrillary threads and tangles, together denoted as NFT, provide the postmortem pathological diagnosis for all tauopathies. In AD, neurofibrillary threads and tangles (NFTs) are codiagnostic with amyloid depositions but their separated and combined contributions to clinical symptoms remain elusive. Importantly, NFTs are now considered a late event and not directly responsible for early synaptic dysfunctions. Conversely, the biochemical and pathological timeline is not exactly known in human tauopathy, but experimental models point to smaller Tau-aggregates, termed oligomers or multimers, as synaptotoxic in early stages. The challenge is to molecularly define these Tau-isoforms that cause early cognitive and synaptic impairments. Here, we discuss relevant studies and data obtained in our mono- and bigenic validated preclinical models, with the perspective of Tau as a therapeutic target.

Early Molecular and Synaptic Dysfunctions In the Prodromal Stages of Alzheimer‘s Disease: Focus on Tnf-α and Il-1β

Alterations in cytokine expression as well as deficits in synaptic activity are two features observed in early, prodromal stages of Alzheimer’s disease (AD). The cytokines TNF-α and IL-1β are not only mediators of immune responses, but are also involved in regulating synaptic activity through their effects on neuronal excitability and Hebbian plasticity. We propose that early changes occurring in the AD brain, such as increases in soluble amyloid-β oligomers, may increase the expression of certain cytokines and subsequently cause alterations in cytokine-mediated synaptic activity. A shift of focus towards the prodromal stages of AD, which incorporate the earliest detectable molecular, electrophysiological and behavioral alterations, may provide novel therapeutic targets and potential biomarkers for this currently incurable neurodegenerative disease.

Interaction between NH2-tau fragment and Aβ in Alzheimer's disease mitochondria contributes to the synaptic deterioration

Although amyloid beta (Aβ) peptide can promote tau pathology and its toxicity is concurrently tau-dependent, the underlying mechanisms of the in vivo interplay of these proteins remain unsolved. Structural and functional mitochondrial alterations play an early, precipitating role in synaptic failure of Alzheimer's disease (AD) pathogenesis and an aggravated mitochondrial impairment has been described in triple APP/PS/tau transgenic mice carrying both plaques and tangles, if compared with mice overexpressing tau or amyloid precursor protein (APP) alone. Here, we show that a neurotoxic aminoterminal (NH2)-derived tau fragment mapping between 26 and 230 amino acids of the human tau40 isoform (441 amino acids)—but not the physiological full-length protein—preferentially interacts with Aβ peptide(s) in human AD synapses in association with mitochondrial adenine nucleotide translocator-1 (ANT-1) and cyclophilin D. The two peptides—Aβ 1–42 and the smaller and more potent NH2-26-44 peptide of the longest 20–22 kDa NH2-tau fragment—inhibit the ANT–1-dependent adenosine diphosphate-adenosine triphosphate (ADP/ATP) exchange in a noncompetitive and competitive manner, respectively, and together further aggravate the mitochondrial dysfunction by exacerbating the ANT-1 impairment. Taken together, these data establish a common, direct and synergistic toxicity of pathological APP and tau products on synaptic mitochondria and suggest potential, new pathway(s) and target(s) for a combined, more efficient therapeutic intervention of early synaptic dysfunction in AD.

Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.

Huntington's disease (HD) is a progressive, fatal neurological condition caused by an expansion of CAG (glutamine) repeats in the coding region of the Huntington gene. To date, there is no cure but great strides have been made to understand pathophysiological mechanisms. In particular, genetic animal models of HD have been instrumental in elucidating the progression of behavioral and physiological alterations, which had not been possible using classic neurotoxin models. Our groups have pioneered the use of transgenic HD mice to examine the excitotoxicity hypothesis of striatal neuronal dysfunction and degeneration, as well as alterations in excitation and inhibition in striatum and cerebral cortex. In this review, we focus on synaptic and receptor alterations of striatal medium-sized spiny (MSNs) and cortical pyramidal neurons in genetic HD mouse models. We demonstrate a complex series of alterations that are region-specific and time-dependent. In particular, many changes are bidirectional depending on the degree of disease progression, that is, early vs. late, and also on the region examined. Early synaptic dysfunction is manifested by dysregulated glutamate release in striatum followed by progressive disconnection between cortex and striatum. The differential effects of altered glutamate release on MSNs originating the direct and indirect pathways is also elucidated, with the unexpected finding that cells of the direct striatal pathway are involved early in the course of the disease. In addition, we review evidence for early N-methyl-D-aspartate receptor (NMDAR) dysfunction leading to enhanced sensitivity of extrasynaptic receptors and a critical role of GluN2B subunits. Some of the alterations in late HD could be compensatory mechanisms designed to cope with early synaptic and receptor dysfunctions. The main findings indicate that HD treatments need to be designed according to the stage of disease progression and should consider regional differences.

Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α‐synuclein

Overexpression or mutation of α-synuclein (α-Syn), a protein associated with presynaptic vesicles, causes familial forms of Parkinson's disease in humans and is also associated with sporadic forms of the disease. We used in vivo microdialysis, tissue content analysis, behavioral assessment, and whole-cell patch clamp recordings from striatal medium-sized spiny neurons (MSSNs) in slices to examine dopamine transmission and dopaminergic modulation of corticostriatal synaptic function in mice overexpressing human wild-type α-Syn under the Thy1 promoter (α-Syn mice). Tonic striatal extracellular dopamine and 3-methoxytyramine levels were elevated in α-Syn mice at 6 months of age, prior to any reduction in total striatal tissue content, and were accompanied by an increase in open-field activity. Dopamine clearance and amphetamine-induced dopamine efflux were unchanged. The frequency of MSSN spontaneous excitatory postsynaptic currents (sEPSCs) was lower in α-Syn mice. Amphetamine reduced sEPSC frequency in wild types (WTs) but produced no effect in α-Syn mice. Furthermore, whereas quinpirole reduced and sulpiride increased sEPSC frequency in WT mice, they produced the opposite effects in α-Syn mice. These observations indicate that overexpression of α-Syn alters dopamine efflux and D2 receptor modulation of corticostriatal glutamate release at a young age. At 14 months of age, the α-Syn mice presented with significantly lower striatal tissue dopamine and tyrosine hydroxylase content relative to WT littermates, accompanied by an L-DOPA-reversible sensory motor deficit. Together, these data further validate this transgenic mouse line as a slowly progressing model of Parkinson's disease and provide evidence for early dopamine synaptic dysfunction prior to loss of striatal dopamine.

Non-Esterified Fatty Acids (NEFAs) Generate Distinct Aβ42 Oligomers via Two Distinct Aggregation Pathways

In Alzheimer's disease (AD), soluble oligomers of amyloid-β (Aβ) are believed to be primary neurotoxic species responsible for early synaptic dysfunction and cognitive decline. The rate of Aβ aggregation is known to be significantly affected in the presence of anionic interfaces such as lipid, fatty acids & other surfactants. Here, we present the effect of saturated non-esterified fatty acids (NEFAs) on the rate of Aβ aggregation. We have observed that NEFAs induce more than one pathway of Aβ aggregation which is dictated by both ratio of Aβ42 : NEFAs as well as NEFAs respective critical micelle concentrations (CMC). More importantly, we observed that irrespective of their carbon chain lengths, NEFAs generate primarily two types of low molecular weight oligomeric species ; a) near CMC concentration, NEFAs increased the rates of Aβ aggregation towards fibril formation that generated 12-18mers, and b) at concentration above CMC, NEFAs failed to show any aggregation and generated 4-5mers, while oligomeric 12-18mers seems to adopt ‘on pathway’ towards fibril formation, the 4-5mers formed via an alternate pathway called ‘off-pathway’ that did not form fibrils. These oligomers generated were characterized using biophysical techniques like thioflavin-T (ThT) fluorescence, immunoblotting, atomic force microscopy (AFM) and circular dichroism (CD). The results from these analyses also showed that these oligomers are generated via two different pathways. All these data are presented and discussed.

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

Synaptic loss is the best pathological correlate of the cognitive decline in Alzheimer's disease; however, the molecular mechanisms underlying synaptic failure are unknown. We found a non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines and an enhancement of this activity at the onset of memory decline in the Tg2576-APPswe mouse model of Alzheimer's disease. In spines, caspase-3 activated calcineurin, which in turn triggered dephosphorylation and removal of the GluR1 subunit of AMPA-type receptor from postsynaptic sites. These molecular modifications led to alterations of glutamatergic synaptic transmission and plasticity and correlated with spine degeneration and a deficit in hippocampal-dependent memory. Notably, pharmacological inhibition of caspase-3 activity in Tg2576 mice rescued the observed Alzheimer-like phenotypes. Our results identify a previously unknown caspase-3-dependent mechanism that drives synaptic failure and contributes to cognitive dysfunction in Alzheimer's disease. These findings indicate that caspase-3 is a potential target for pharmacological therapy during early disease stages.

Dynamics of protofibril elongation and association involved in Aβ42 peptide aggregation in Alzheimer’s disease

BackgroundThe aggregates of a protein called, ‘Aβ’ found in brains of Alzheimer’s patients are strongly believed to be the cause for neuronal death and cognitive decline. Among the different forms of Aβ aggregates, smaller aggregates called ‘soluble oligomers’ are increasingly believed to be the primary neurotoxic species responsible for early synaptic dysfunction. Since it is well known that the Aβ aggregation is a nucleation dependant process, it is widely believed that the toxic oligomers are intermediates to fibril formation, or what we call the ‘on-pathway’ products. Modeling of Aβ aggregation has been of intense investigation during the last decade. However, precise understanding of the process, pre-nucleation events in particular, are not yet known. Most of these models are based on curve-fitting and overlook the molecular-level biophysics involved in the aggregation pathway. Hence, such models are not reusable, and fail to predict the system dynamics in the presence of other competing pathways.ResultsIn this paper, we present a molecular-level simulation model for understanding the dynamics of the amyloid-β (Aβ) peptide aggregation process involved in Alzheimer’s disease (AD). The proposed chemical kinetic theory based approach is generic and can model most nucleation-dependent protein aggregation systems that cause a variety of neurodegenerative diseases. We discuss the challenges in estimating all the rate constants involved in the aggregation process towards fibril formation and propose a divide and conquer strategy by dissecting the pathway into three biophysically distinct stages: 1) pre-nucleation stage 2) post-nucleation stage and 3) protofibril elongation stage. We next focus on estimating the rate constants involved in the protofibril elongation stages for Aβ42 supported by in vitro experimental data. This elongation stage is further characterized by elongation due to oligomer additions and lateral association of protofibrils (13) and to properly validate the rate constants involved in these phases we have presented three distinct reaction models. We also present a novel scheme for mapping the fluorescence sensitivity and dynamic light scattering based in vitro experimental plots to estimates of concentration variation with time. Finally, we discuss how these rate constants will be incorporated into the overall simulation of the aggregation process to identify the parameters involved in the complete Aβ pathway in a bid to understand its dynamics.ConclusionsWe have presented an instance of the top-down modeling paradigm where the biophysical system is approximated by a set of reactions for each of the stages that have been modeled. In this paper, we have only reported the kinetic rate constants of the fibril elongation stage that were validated by in vitro biophysical analyses. The kinetic parameters reported in the paper should be at least accurate upto the first two decimal places of the estimate. We sincerely believe that our top-down models and kinetic parameters will be able to accurately model the biophysical phenomenon of Aβ protein aggregation and identify the nucleation mass and rate constants of all the stages involved in the pathway. Our model is also reusable and will serve as the basis for making computational predictions on the system dynamics with the incorporation of other competing pathways introduced by lipids and fatty acids.

Dysfunction and recovery of synapses in prion disease: implications for neurodegeneration

Synaptic dysfunction is a key early process in many neurodegenerative diseases, but how this ultimately leads to neuronal loss is not clear. In health, there is ongoing remodelling of synapses and spines in the adult brain: their elimination and formation are continual physiological processes fundamental to learning and memory. But in neurodegenerative disease, including prion disease, lost synapses are not replaced, and their loss is followed by neuronal death. These two processes are separately regulated, with mechanistic, spatial and temporal segregation of the respective death routines of synapses and cell bodies. Mice with prion disease can be cured at the stage of early synaptic dysfunction, when they have reversible impairments at neurophysiological, behavioural and morphological levels. Critically, reversing synaptic dysfunction at this stage of disease rescues neurons, preventing its otherwise inevitable progression to synapse loss and cell death. These findings call for a deeper analysis of the mechanisms underlying neurotoxicity at the synapse, and have important implications for the therapy of prion and other neurodegenerative disorders.

Change in tau phosphorylation associated with neurodegeneration in the ME7 model of prion disease

Hyperphosphorylation of the microtubule-associated protein tau is a significant determinant in AD (Alzheimer's disease), where it is associated with disrupted axonal transport and probably causes synaptic dysfunction. Although less well studied, hyperphosphorylation has been observed in prion disease. We have investigated the expression of hyperphosphorylated tau in the hippocampus of mice infected with the ME7 prion agent. In ME7-infected animals, there is a selective loss of CA1 synapse, first discernable at 13 weeks of disease. There is a potential that dysfunctional axonal transport contributes to this synaptopathy. Thus investigating hyperphosphorylated tau that is dysfunctional in AD could illuminate whether and how they are significant in prion disease. We observed no differences in the levels of phosphorylated tau (using MC1, PHF-1 and CP13 antibodies) in detergent-soluble and detergent-insoluble fractions extracted from ME7- and NBH- (normal brain homogenate) treated animals across disease. In contrast, we observed an increase in phospho-tau staining for several epitopes using immunohistochemistry in ME7-infected hippocampal sections. Although the changes were not of the magnitude seen in AD tissue, clear differences for several phospho-tau species were seen in the CA1 and CA3 of ME7-treated animals (pSer(199-202)>pSer(214)>PHF-1 antibody). Temporally, these changes were restricted to animals at 20 weeks and none of the disease-related staining was associated with the axons or dendrites that hold CA1 synapses. These findings suggest that phosphorylation of tau at the epitopes examined does not underpin the early synaptic dysfunction. These data suggest that the changes in tau phosphorylation recorded here and observed by others relate to end-stage prion pathology when early dysfunctions have progressed to overt neuronal loss.

Effects of Fatty Acids and Phospholipids on Amyloid-β (Aβ) Peptide Aggregation

The aggregates of Aβ found in brains of Alzheimer's patients are strongly believed to be the cause for neuronal death and cognitive decline. Among the different forms of Aβ aggregates, smaller aggregates called ‘soluble oligomers’ are increasingly believed to be the primary neurotoxic species responsible for early synaptic dysfunction. Since it is well known that the Aβ aggregation is a nucleation dependant process, it is widely believed that the toxic oligomers are intermediates to fibril formation, or what we call the ‘on-pathway’ products. Although it is true that there may be toxic oligomers along the fibril formation pathway, it is not obligatory that all toxic oligomers must be ‘on-pathway’ intermediates. It is important to understand the pathways because if the oligomers are ‘off-pathway’ products, their half-life can be significantly longer than the ‘on-pathway’ ones that may result in prolonged toxicity to the neuronal cells. Here, we test this hypothesis in the presence of saturated fatty acids and phosphatidylglycerol lipids by varying their carbon chain lengths. We observed that Aβ aggregation can adopt more than one pathway, and the pathway is dictated by Aβ-fatty acid/lipid ratio. Oligomers generated from lipids and fatty acids were isolated and characterized using thioflavin-T (ThT) fluorescence, immunoblotting and atomic force microscopy (AFM). These data are presented and discussed.

Alpha‐synuclein overexpression in mice alters synaptic communication in the corticostriatal pathway

alpha-Synuclein (alpha-Syn) is a presynaptic protein implicated in Parkinson's disease (PD). Mice overexpressing human wildtype (WT) alpha-Syn under the Thy1 promoter show high levels of alpha-Syn in cortical and subcortical regions, exhibit progressive sensorimotor anomalies, as well as non-motor abnormalities and are considered models of pre-manifest PD as there is little evidence of early loss of dopaminergic (DA) neurons. We used whole-cell patch clamp recordings from visually identified striatal medium-sized spiny neurons (MSSNs) in slices from alpha-Syn and WT littermate control mice at 35, 90 and 300 days of age to examine corticostriatal synaptic function. MSSNs displayed significant decreases in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in alpha-Syn mice at all ages. This difference persisted in the presence of tetrodotoxin, indicating it was independent of action potentials. Stimulation thresholds for evoking EPSCs were significantly higher and responses were smaller in alpha-Syn mice. These data suggest a decrease in neurotransmitter release at the corticostriatal synapse. At 90 days the frequency of spontaneous GABA(A) receptor-mediated synaptic currents was decreased in MSSNs but increased in cortical pyramidal neurons. These observations indicate that high levels of expression of alpha-Syn alter corticostriatal synaptic function early and they provide evidence for early synaptic dysfunction in a pre-manifest model of PD. Of importance, these changes are opposite to those found in DA-depletion models, suggesting that before degeneration of DA neurons in the substantia nigra synaptic adaptations occur at the corticostriatal synapse that may initiate subtle preclinical manifestations.

Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses

Accumulation of cerebral amyloid-beta peptide (Abeta) is essential for developing synaptic and cognitive deficits in Alzheimer's disease. However, the physiological functions of Abeta, as well as the primary mechanisms that initiate early Abeta-mediated synaptic dysfunctions, remain largely unknown. Here we examine the acute effects of endogenously released Abeta peptides on synaptic transfer at single presynaptic terminals and synaptic connections in rodent hippocampal cultures and slices. Increasing extracellular Abeta by inhibiting its degradation enhanced release probability, boosting ongoing activity in the hippocampal network. Presynaptic enhancement mediated by Abeta was found to depend on the history of synaptic activation, with lower impact at higher firing rates. Notably, both elevation and reduction in Abeta levels attenuated short-term synaptic facilitation during bursts in excitatory synaptic connections. These observations suggest that endogenous Abeta peptides have a crucial role in activity-dependent regulation of synaptic vesicle release and might point to the primary pathological events that lead to compensatory synapse loss in Alzheimer's disease.

Synthetic Abeta 1-40 oligomers impair recognition memory in mice

Alzheimer disease (AD) is a neurodegenerative pathology characterized by cerebral β-amyloid (Aβ) deposits, neurofibrillary tangles, early synaptic dysfunction and subsequent memory loss. Aβ oligomers, rather than fibrils, were proposed to play a major role in the neurodegeneration. Various forms of Aβ oligomers extracted from the brain were shown to induce synaptic failure and cognitive impairment. Aβ oligomers inhibited the long-term potentiation (LTP) process, a paradigm measuring synaptic plasticity, and induced loss of dendritic spines which represent synaptic connections in the formation of new memory traces. The present study was aimed to investigate, in vivo, the effect of synthetic Aβ1-40 monomer, small oligomers and higher aggregates, in mice tested in the object recognition task. Aβ oligomers were covalently stabilized using the photo-induced-cross-linking technique. Two hours following Aβ1-40 (1.0 μM) intracerebroventricle (icv) injection, mice underwent to the familiarization phase on day 1 and to the memory test phase on day 2. Memory abilities were determined calculating the discrimination index. Our findings show that only Aβ1-40 oligomers have the ability to impair long-term recognition memory. Moreover, we demonstrated that this effect was reverted by an icv pretreatment with the 4G8 anti-Aβ antibody. Our findings demonstrate, in vivo, that beside Aβ1-42 also synthetic Aβ1-40 oligomers have toxic effects on cognitive processes. Furthermore, the ability of the Aβ specific antibody to revert Aβ1-40-mediated cognitive impairment, supports the immunotherapy as useful strategy in the AD pathology.

Synthetic Abeta 1-40 oligomers impair recognition memory in mice

Alzheimer disease (AD) is a neurodegenerative pathology characterized by cerebral β-amyloid (Aβ) deposits, neurofibrillary tangles, early synaptic dysfunction and subsequent memory loss. Aβ oligomers, rather than fibrils, were proposed to play a major role in the neurodegeneration. Various forms of Aβ oligomers extracted from the brain were shown to induce synaptic failure and cognitive impairment. Aβ oligomers inhibited the long-term potentiation (LTP) process, a paradigm measuring synaptic plasticity, and induced loss of dendritic spines which represent synaptic connections in the formation of new memory traces. The present study was aimed to investigate, in vivo, the effect of synthetic Aβ1-40 monomer, small oligomers and higher aggregates, in mice tested in the object recognition task. Aβ oligomers were covalently stabilized using the photo-induced-cross-linking technique. Two hours following Aβ1-40 (1.0 μM) intracerebroventricle (icv) injection, mice underwent to the familiarization phase on day 1 and to the memory test phase on day 2. Memory abilities were determined calculating the discrimination index. Our findings show that only Aβ1-40 oligomers have the ability to impair long-term recognition memory. Moreover, we demonstrated that this effect was reverted by an icv pretreatment with the 4G8 anti-Aβ antibody. Our findings demonstrate, in vivo, that beside Aβ1-42 also synthetic Aβ1-40 oligomers have toxic effects on cognitive processes. Furthermore, the ability of the Aβ specific antibody to revert Aβ1-40-mediated cognitive impairment, supports the immunotherapy as useful strategy in the AD pathology.

Selective induction of calcineurin activity and signaling by oligomeric amyloid beta

Alzheimer's disease (AD) is a terminal age-associated dementia characterized by early synaptic dysfunction and late neurodegeneration. Although the presence of plaques of fibrillar aggregates of the amyloid beta peptide (Abeta) is a signature of AD, evidence suggests that the preplaque small oligomeric Abeta promotes both synaptic dysfunction and neuronal death. We found that young Tg2576 transgenic mice, which accumulate Abeta and develop cognitive impairments prior to plaque deposition, have high central nervous system (CNS) activity of calcineurin (CaN), a phosphatase involved in negative regulation of memory function via inactivation of the transcription factor cAMP responsive element binding proteins (CREB), and display CaN-dependent memory deficits. These results thus suggested the involvement of prefibrillary forms of Abeta. To investigate this issue, we compared the effect of monomeric, oligomeric, and fibrillar Abeta on CaN activity, CaN-dependent pCREB and phosphorylated Bcl-2 Associated death Protein (pBAD) levels, and cell death in SY5Y cells and in rat brain slices, and determined the role of CaN on CREB phosphorylation in the CNS of Tg2576 mice. Our results show that oligomeric Abeta specifically induces CaN activity and promotes CaN-dependent CREB and Bcl-2 Asociated death Protein (BAD) dephosphorylation and cell death. Furthermore, Tg2576 mice display Abeta oligomers and reduced pCREB in the CNS, which is normalized by CaN inhibition. These findings suggest a role for CaN in mediating effects of oligomeric Abeta on neural cells. Because elevated CaN levels have been reported in the CNS of cognitively impaired aged rodents, our results further suggest that abnormal CaN hyperactivity may be a common event exacerbating the cognitive and neurodegenerative impact of oligomeric Abeta in the aging CNS.