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Hippocampal neuronal activity generates dendritic and somatic Ca2+ signals, which, depending on stimulus intensity, rapidly propagate to the nucleus and induce the expression of transcription factors and genes with crucial roles in cognitive functions. Soluble amyloid-beta oligomers (AβOs), the main synaptotoxins engaged in the pathogenesis of Alzheimer's disease, generate aberrant Ca2+ signals in primary hippocampal neurons, increase their oxidative tone and disrupt structural plasticity. Here, we explored the effects of sub-lethal AβOs concentrations on activity-generated nuclear Ca2+ signals and on the Ca2+-dependent expression of neuroprotective genes. To induce neuronal activity, neuron-enriched primary hippocampal cultures were treated with the GABAA receptor blocker gabazine (GBZ), and nuclear Ca2+ signals were measured in AβOs-treated or control neurons transfected with a genetically encoded nuclear Ca2+ sensor. Incubation (6 h) with AβOs significantly reduced the nuclear Ca2+ signals and the enhanced phosphorylation of cyclic AMP response element-binding protein (CREB) induced by GBZ. Likewise, incubation (6 h) with AβOs significantly reduced the GBZ-induced increases in the mRNA levels of neuronal Per-Arnt-Sim domain protein 4 (Npas4), brain-derived neurotrophic factor (BDNF), ryanodine receptor type-2 (RyR2), and the antioxidant enzyme NADPH-quinone oxidoreductase (Nqo1). Based on these findings we propose that AβOs, by inhibiting the generation of activity-induced nuclear Ca2+ signals, disrupt key neuroprotective gene expression pathways required for hippocampal-dependent learning and memory processes. [ABSTRACT FROM AUTHOR]

The canonical mechanism of organophosphate (OP) neurotoxicity is the inhibition of acetylcholinesterase (AChE). However, multiple lines of evidence suggest that mechanisms in addition to or other than AChE inhibition contribute to the neurotoxic effects associated with acute and chronic OP exposures. Characterizing the role(s) of AChE inhibition versus noncholinergic mechanisms in OP neurotoxicity remains an active area of research with significant diagnostic and therapeutic implications. Here, we review recently published studies that provide mechanistic insights regarding (1) OP-induced status epilepticus, (2) long-term neurologic consequences of acute OP exposures, and (3) neurotoxic effects associated with repeated low-level OP exposures. Key data gaps and challenges are also discussed.

Hippocampal neuronal activity generates dendritic and somatic Ca2+ signals, which, depending on stimulus intensity, rapidly propagate to the nucleus and induce the expression of transcription factors and genes with crucial roles in cognitive functions. Soluble amyloid-beta oligomers (AβOs), the main synaptotoxins engaged in the pathogenesis of Alzheimer’s disease, generate aberrant Ca2+ signals in primary hippocampal neurons, increase their oxidative tone and disrupt structural plasticity. Here, we explored the effects of sub-lethal AβOs concentrations on activity-generated nuclear Ca2+ signals and on the Ca2+-dependent expression of neuroprotective genes. To induce neuronal activity, neuron-enriched primary hippocampal cultures were treated with the GABAA receptor blocker gabazine (GBZ), and nuclear Ca2+ signals were measured in AβOs-treated or control neurons transfected with a genetically encoded nuclear Ca2+ sensor. Incubation (6 h) with AβOs significantly reduced the nuclear Ca2+ signals and the enhanced phosphorylation of cyclic AMP response element-binding protein (CREB) induced by GBZ. Likewise, incubation (6 h) with AβOs significantly reduced the GBZ-induced increases in the mRNA levels of neuronal Per-Arnt-Sim domain protein 4 (Npas4), brain-derived neurotrophic factor (BDNF), ryanodine receptor type-2 (RyR2), and the antioxidant enzyme NADPH-quinone oxidoreductase (Nqo1). Based on these findings we propose that AβOs, by inhibiting the generation of activity-induced nuclear Ca2+ signals, disrupt key neuroprotective gene expression pathways required for hippocampal-dependent learning and memory processes.

Aqueously soluble oligomers of amyloid-β peptide may be the principal neurotoxic forms of amyloid-β in Alzheimer's disease, initiating downstream events that include tau hyperphosphorylation, neuritic/synaptic injury, microgliosis and neuron loss. Synthetic oligomeric amyloid-β has been studied extensively, but little is known about the biochemistry of natural oligomeric amyloid-β in human brain, even though it is more potent than simple synthetic peptides and comprises truncated and modified amyloid-β monomers. We hypothesized that monoclonal antibodies specific to neurotoxic oligomeric amyloid-β could be used to isolate it for further study. Here we report a unique human monoclonal antibody (B24) raised against synthetic oligomeric amyloid-β that potently prevents Alzheimer's disease brain oligomeric amyloid-β-induced impairment of hippocampal long-term potentiation. B24 binds natural and synthetic oligomeric amyloid-β and a subset of amyloid plaques, but only in the presence of Ca2+. The amyloid-β N terminus is required for B24 binding. Hydroxyapatite chromatography revealed that natural oligomeric amyloid-β is highly avid for Ca2+. We took advantage of the reversible Ca2+-dependence of B24 binding to perform non-denaturing immunoaffinity isolation of oligomeric amyloid-β from Alzheimer's disease brain-soluble extracts. Unexpectedly, the immunopurified material contained amyloid fibrils visualized by electron microscopy and amenable to further structural characterization. B24-purified human oligomeric amyloid-β inhibited mouse hippocampal long-term potentiation. These findings identify a calcium-dependent method for purifying bioactive brain oligomeric amyloid-β, at least some of which appears fibrillar. [ABSTRACT FROM AUTHOR]

Pathological hallmarks of Alzheimer's disease (AD) include deposition and accumulation of amyloid- β (Aβ), neurofibrillary tangle formation, and neuronal loss. Pathogenesis of presymptomatic disease stages remains elusive, although studies suggest that the early structural and functional alterations likely occur at neuronal dendritic spines. Presymptomatic alterations may also affect different CNS cell types. However, specific contributions of these cell types as cause or consequence of pathology are difficult to study in vivo. There is a shortage of relatively simple, well-defined, and validated in vitro models that allow a straightforward interpretation of results and recapitulate aspects of pathophysiology. For instance, dissecting the AD-related processes (e.g., neurotoxicity vs. synaptotoxicity) may be difficult with the common cell-based systems such as neuronal cell lines or primary neurons. To investigate and characterize the impact of reactive astrocytes on neuronal morphology in the context of AD-related cues, we modified an in vitro co-culture assay of primary mouse neurons and primary mouse astrocytes based on the so-called Banker "sandwich" co-culture assay. Here, we provide a simple and modular assay with fully differentiated primary mouse neurons to study the paracrine interactions between the neurons and the astrocytes in the co-culture setting. Readouts were obtained from both cell types in our assay. Astrocyte feeder cells were pre-exposed to neuroinflammatory conditions by means of Aβ42, Aβ40, or lipopolysaccharide (LPS). Non-cell autonomous toxic effects of reactive astrocytes on neurons were assessed using the Sholl analysis to evaluate the dendritic complexity, whereas synaptic puncta served as a readout of synaptotoxicity. Here, we show that astrocytes actively contribute to the phenotype of the primary neurons in an AD-specific context, emphasizing the role of different cell types in AD pathology. The cytokine expression pattern was significantly altered in the treated astrocytes. Of note, the impact of reactive astrocytes on neurons was highly dependent on the defined cell ratios. Our co-culture system is modular, of low cost, and allows us to probe aspects of neurodegeneration and neuroinflammation between the two major CNS cell types, neurons, and astrocytes, under well-defined experimental conditions. Our easy-to-follow protocol, including work-flow figures, may also provide a methodological outline to study the interactions of astrocytes and neurons in the context of other diseases in the future. [ABSTRACT FROM AUTHOR]

Pathological hallmarks of Alzheimer’s disease (AD) include deposition and accumulation of amyloid- β (Aβ), neurofibrillary tangle formation, and neuronal loss. Pathogenesis of presymptomatic disease stages remains elusive, although studies suggest that the early structural and functional alterations likely occur at neuronal dendritic spines. Presymptomatic alterations may also affect different CNS cell types. However, specific contributions of these cell types as cause or consequence of pathology are difficult to study in vivo. There is a shortage of relatively simple, well-defined, and validated in vitro models that allow a straightforward interpretation of results and recapitulate aspects of pathophysiology. For instance, dissecting the AD-related processes (e.g., neurotoxicity vs. synaptotoxicity) may be difficult with the common cell-based systems such as neuronal cell lines or primary neurons. To investigate and characterize the impact of reactive astrocytes on neuronal morphology in the context of AD-related cues, we modified an in vitro co-culture assay of primary mouse neurons and primary mouse astrocytes based on the so-called Banker “sandwich” co-culture assay. Here, we provide a simple and modular assay with fully differentiated primary mouse neurons to study the paracrine interactions between the neurons and the astrocytes in the co-culture setting. Readouts were obtained from both cell types in our assay. Astrocyte feeder cells were pre-exposed to neuroinflammatory conditions by means of Aβ42, Aβ40, or lipopolysaccharide (LPS). Non-cell autonomous toxic effects of reactive astrocytes on neurons were assessed using the Sholl analysis to evaluate the dendritic complexity, whereas synaptic puncta served as a readout of synaptotoxicity. Here, we show that astrocytes actively contribute to the phenotype of the primary neurons in an AD-specific context, emphasizing the role of different cell types in AD pathology. The cytokine expression pattern was significantly altered in the treated astrocytes. Of note, the impact of reactive astrocytes on neurons was highly dependent on the defined cell ratios. Our co-culture system is modular, of low cost, and allows us to probe aspects of neurodegeneration and neuroinflammation between the two major CNS cell types, neurons, and astrocytes, under well-defined experimental conditions. Our easy-to-follow protocol, including work-flow figures, may also provide a methodological outline to study the interactions of astrocytes and neurons in the context of other diseases in the future.

• GPR139 activation in the brain ameliorated Aβ 1-42 -induced cognitive impairment. • GPR139 activation alleviated Aβ 1-42 -induced apoptosis and synaptotoxicity in the basal forebrain. • GPR139 overexpression in the MS ameliorated cognitive impairment in APP/PS1 mice. • GPR139 overexpression in the MS alleviated apoptosis and synaptotoxicity in APP/PS1 mice. G-protein coupled receptors (GPCRs) constitute the largest class of cell surface receptors and present prominent drug targets. GPR139 is an orphan GPCR detected in the septum of the brain. However, its roles in cognition are still unclear. Here we first established a mouse model of cognitive impairment by a single intracerebroventricular injection of aggregated amyloid-beta peptide 1–42 (Aβ 1-42). RNA-sequencing data analysis showed that Aβ 1-42 induced a significant decrease of GPR139 mRNA in the basal forebrain. Using GPR139 agonist JNJ-63533054 and behavioral tests, we found that GPR139 activation in the brain ameliorated Aβ 1-42 -induced cognitive impairment. Using western blot, TUNEL apoptosis and Golgi staining assays, we showed that GPR139 activation alleviated Aβ 1-42 -induced apoptosis and synaptotoxicity in the basal forebrain rather than prefrontal cortex and hippocampus. The further study identified that GPR139 was widely expressed in cholinergic neurons of the medial septum (MS). Using the overexpression virus and transgenic animal model, we showed that up-regulation of GPR139 in MS cholinergic neurons ameliorated cognitive impairment, apoptosis and synaptotoxicity in APP/PS1 transgenic mice. These findings reveal that GPR139 of MS cholinergic neurons could be a critical node in cognition and potentially provides insight into the pathogenesis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Among Alzheimer's disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity and the outcomes of astrocyte reactivity are far from being completely elucidated. Another key role in AD pathogenesis is played by alterations in brain cholesterol metabolism. Oxysterols (cholesterol oxidation products) are crucial for brain cholesterol homeostasis, and we previously demonstrated that changes in the brain levels of various oxysterols correlate with AD progression. Moreover, oxysterols have been shown to contribute to various pathological mechanisms involved in AD pathogenesis. In order to deepen the role of oxysterols in AD, we investigated whether they could contribute to astrocyte reactivity, and consequently impact on neuronal health. Results showed that oxysterols present in mild or severe AD brains induce a clear morphological change in mouse primary astrocytes, accompanied by the upregulation of some reactive astrocyte markers, including lipocalin-2 (Lcn2). Moreover, astrocyte conditioned media analysis revealed a significant increase in the release of Lcn2, cytokines, and chemokines in response to oxysterols. A significant reduction of postsynaptic density protein 95 (PSD95) and a concurrent increase in cleaved caspase-3 protein levels have been demonstrated in neurons co-cultured with oxysterol-treated astrocytes, pointing out that mediators released by astrocytes have an impact on neurons. Among these mediators, Lcn2 has been demonstrated to play a major role on synapses, affecting neurite morphology and decreasing dendritic spine density. These data demonstrated that oxysterols present in the AD brain promote astrocyte reactivity, determining the release of several mediators that affect neuronal health and synapses. Lcn2 has been shown to exert a key role in mediating the synaptotoxic effect of oxysterol-treated astrocytes.

Alzheimer's disease (AD) is a neurodegenerative disease and the most frequent cause of dementia. It is characterized by the accumulation in the brain of two pathological protein aggregates: amyloid-β peptides (Aβ) and abnormally phosphorylated tau. The progressive cognitive decline observed in patients strongly correlates with the synaptic loss. Many lines of evidence suggest that soluble forms of Aβ accumulate into the brain where they cause synapse degeneration. Stopping their spreading and/or targeting the pathophysiological mechanisms leading to synaptic loss would logically be beneficial for the patients. However, we are still far from understanding these processes. Our objective was therefore to develop a versatile model to assay and study Aβ-induced synaptotoxicity. We integrated a microfluidic device that physically isolates synapses from presynaptic and postsynaptic neurons with a microelectrode array. We seeded mouse primary cortical cells in the presynaptic and postsynaptic chambers. After functional synapses have formed in the synaptic chamber, we exposed them to concentrated conditioned media from cell lines overexpressing the wild-type or mutated amyloid precursor protein and thus secreting different levels of Aβ. We recorded the neuronal activity before and after exposition to Aβ and quantified Aβ's effects on the connectivity between presynaptic and postsynaptic neurons. We observed that the application of Aβ on the synapses for 48 h strongly decreased the interchamber connectivity without significantly affecting the neuronal activity in the presynaptic or postsynaptic chambers. Thus, through this model, we are able to functionally assay the impact of Aβ peptides (or other molecules) on synaptic connectivity and to use the latter as a proxy to study Aβ-induced synaptotoxicity. Moreover, since the presynaptic, postsynaptic, and synaptic chambers can be individually targeted, our assay provides a powerful tool to evaluate the involvement of candidate genes in synaptic vulnerability and/or test therapeutic strategies for AD.

Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not currently understood. Although CAA is highly associated with the accumulation of β‐amyloid (Aβ), other amyloids are known to associate with the vasculature. Alzheimer's disease (AD) is characterized by parenchymal Aβ deposition and intracellular accumulation of tau as neurofibrillary tangles (NFTs), affecting synapses directly, leading to behavioral and physical impairment. CAA increases with age and is present in 70%–97% of individuals with AD. Studies have overwhelmingly focused on the connection between parenchymal amyloid accumulation and synaptotoxicity; thus, the contribution of vascular amyloid is mostly understudied. Here, synaptic alterations induced by vascular amyloid accumulation and their behavioral consequences were characterized using a mouse model of Familial Danish dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature. The mouse model (Tg‐FDD) displays a hyperactive phenotype that potentially arises from impairment in the GABAergic synapses, as determined by electrophysiological analysis. We demonstrated that the disruption of GABAergic synapse organization causes this impairment and provided evidence that GABAergic synapses are impaired in patients with CAA pathology. Understanding the mechanism that CAA contributes to synaptic dysfunction in AD‐related dementias is of critical importance for developing future therapeutic interventions. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which is clinically associated with a global cognitive decline and progressive loss of memory and reasoning. According to the prevailing amyloid cascade hypothesis of AD, increased soluble amyloid-β (Aβ) oligomer levels impair the synaptic functions and augment calcium dyshomeostasis, neuroinflammation, oxidative stress as well as the formation of neurofibrillary tangles at specific brain regions. Emerging new findings related to synaptic dysfunction and initial steps of neuroinflammation in AD have been able to delineate the underlying molecular mechanisms, thus reinforcing the development of new treatment strategies and biomarkers for AD beyond the conventional Aβ- and tau-targeted approaches. Particularly, the identification and further characterization of disease-associated microglia and their RNA signatures, AD-associated novel risk genes, neurotoxic astrocytes, and in the involvement of complement-dependent pathway in synaptic pruning and loss in AD have set the outstanding basis for further preclinical and clinical studies. Here, we discuss the recent development and the key findings related to the novel molecular mechanisms and targets underlying the synaptotoxicity and neuroinflammation in AD.

Alzheimer's disease (AD) is characterized by progressive memory loss and dementia. The strong correlation between cognitive decline and the loss of synapses supports the idea that synaptic damage is a relevant pathogenic mechanism underlying AD progression. It has been shown that amyloid beta oligomers (AβOs) induce synaptotoxicity ultimately leading to the reduction of dendritic spine density, which underlies cognitive damage. However, the signaling pathways connecting AβOs to synaptic dysfunction have not been completely elucidated. In this review, we have gathered evidence on AβOs receptors and the signaling pathways involved in synaptic damage. We make special emphasis on a new AβOs induced axis that involves the tyrosine kinase ephrin receptor A4 (EphA4) and c-Abl tyrosine kinase activation. EphA4 is a key player in homeostatic plasticity, mediating dendritic spine remodeling and retraction. AβOs aberrantly activate EphA4 leading to dendritic spine elimination. c-Abl is activated in AβOs exposed neurons and in AD patient's brain, and the inhibition of activated c-Abl ameliorates cognitive deficits in AD mouse model. The EphA4 receptor activates c-Abl intracellular signaling. Therefore EphA4 is an emerging AβOs receptor and the activation of the EphA4/c-Abl axis would explain the synaptic spine alterations found in AD. [ABSTRACT FROM AUTHOR]

Introduction: Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid β (Aβ) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aβ induces Dickkopf‐1 (Dkk1), which in turn activates the Wnt–planar cell polarity (Wnt‐PCP) pathway to drive tau pathology and neuronal death. Methods: We compared the effects of Aβ and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt‐PCP pathway. Results: We demonstrate that Aβ synaptotoxicity is also Dkk1 and Wnt‐PCP dependent, mediated by the arm of Wnt‐PCP regulating actin cytoskeletal dynamics via Daam1, RhoA and ROCK, and can be blocked by the drug fasudil. Discussion: Our data add to the importance of aberrant Wnt signaling in Alzheimer's disease neuropathology and indicate that fasudil could be repurposed as a treatment for the disease. Highlights: Aβ synaptotoxicity is Dickkopf‐1 and Wnt‐PCP dependent.The Wnt‐PCP pathway drives Aβ‐driven synapse loss via RhoA and ROCK.ROCK inhibitor fasudil blocks Aβ‐driven synapse loss and cognitive impairment.Fasudil should be assessed for repurposing for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The adenosine modulation system mostly operates through inhibitory A1 (A1R) and facilitatory A2A receptors (A2AR) in the brain. The activity-dependent release of adenosine acts as a brake of excitatory transmission through A1R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: high-frequency stimulation triggers ATP release in the 'activated' synapse, which is locally converted by ecto-nucleotidases into adenosine to selectively activate A2AR; A2AR switch off A1R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the 'activated' synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A1R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near-threshold and/or of short-duration, A1R trigger preconditioning, which may limit the spread of damage. Brain insults also up-regulate A2AR, probably to bolster adaptive changes, but this heightens brain damage since A2AR blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A2AR, whereas astrocytic and microglia A2AR might control the spread of damage. The A2AR signaling mechanisms are largely unknown since A2AR are pleiotropic, coupling to different G proteins and non-canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A1R preconditioning and preventing excessive A2AR function might afford maximal neuroprotection. [ABSTRACT FROM AUTHOR]

β-amyloid (Aβ)-mediated neuronal apoptosis contributes to the pathogenesis of Alzheimer's disease (AD). This study aimed to investigate whether astragalosides (AST) could inhibit Aβ-induced apoptosis in vivo and in vitro and to explore the underlying mechanisms. Amyloid β-protein fragment 25-35 (Aβ) was administered to cerebral lateral ventricle of rats to make the AD models in vivo. AST was able to attenuate both cortical cell degeneration and memory deficits in the AD rats. AST also inhibited Aβ-induced cytotoxicity (e.g., decreased cell viability); apoptosis (e.g., increased caspase-3 expression, increased DNA fragmentation, and Tau hyperphosphorylation); synaptotoxicity (e.g., increased loss of both a dendritic marker, microtubule-associated protein 2 (MAP-2) and synaptic proteins, synaptophysins); and mitochondrial dysfunction (e.g., increased mitochondrial membrane potential) in cultured primary rat cortical cells. The beneficial effect of AST in reducing Aβ-induced cytotoxicity, apoptosis, and mitochondrial dysfunction in cortical cells were blocked by inhibition of phosphoinositide 3-kinase (PI3K)-dependent protein kinase B (PKB, as known as AKT) activation with LY294002. In addition, inhibition of extracellular protein kinase (ERK) with U0126 shared with the AST the same beneficial effects in reducing Aβ-induced apoptosis. Our data suggest that the cortical PI3K/AKT and MAPK (or ERK) pathways as appealing therapeutic targets in treating AD, and AST may have a positive impact on AD treatment via modulation of both PI3K/AKT and ERK pathways. [ABSTRACT FROM AUTHOR]

Early-stage Alzheimer's disease (AD) is characterized by synaptic dysfunction, a phenomenon in which soluble oligomers of amyloid-beta (Aβ) and N-methyl-D-aspartate receptor (NMDAR) are implicated. Here, we demonstrated that astrocytes express NMDARs and therefore have the potential to modulate the synaptotoxic actions of Aβ. We found that specific pharmacological antagonism of two of the major NMDAR subunits, GluN2A and GluN2B, exacerbates Aβ-induced synaptotoxicity suggesting, for the first time, that astrocytic GluN2A and GluN2B mediate synaptoprotection. From the perspective of the pathogenic mechanisms of Alzheimer's disease, in which Aβ and NMDAR play significant roles, these observations are striking since neuronal GluN2A and GluN2B are well known modulators of neurodegeneration. We did initial studies to understand the basis for the differential effects of astrocytic and neuronal GluN2A and GluN2B in the promotion of synapse survival, and identified a neurotrophin produced by astrocytes, nerve growth factor β (β-NGF), as a likely mediator of the synaptoprotective effects of astrocytic GluN2A and GluN2B activation. The results presented suggest that astrocytes may be suitable druggable targets for the prevention and/or delay of the synaptic loss that occurs during early stages of AD. [ABSTRACT FROM AUTHOR]

Membrane-type 5-matrix metalloproteinase (MT5-MMP) is a proteinase mainly expressed in the nervous system with emerging roles in brain pathophysiology. The implication of MT5-MMP in Alzheimer's disease (AD), notably its interplay with the amyloidogenic process, remains elusive. Accordingly, we crossed the genetically engineered 5xFAD mouse model of AD with MT5-MMP-deficient mice and examined the impact of MT5-MMP deficiency in bigenic 5xFAD/MT5-MMP mice. At early stages (4 months) of the pathology, the levels of amyloid beta peptide (Aβ) and its amyloid precursor protein (APP) C-terminal fragment C99 were largely reduced in the cortex and hippocampus of 5xFAD/MT5-MMP, compared to 5xFAD mice. Reduced amyloidosis in bigenic mice was concomitant with decreased glial reactivity and interleukin-1β (IL-1β) levels, and the preservation of long-term potentiation (LTP) and spatial learning, without changes in the activity of α-, β- and γ-secretases. The positive impact of MT5-MMP deficiency was still noticeable at 16 months of age, as illustrated by reduced amyloid burden and gliosis, and a better preservation of the cortical neuronal network and synaptophysin levels in bigenic mice. MT5-MMP expressed in HEKswe cells colocalized and co-immunoprecipitated with APP and significantly increased the levels of Aβ and C99. MT5-MMP also promoted the release of a soluble APP fragment of 95 kDa (sAPP95) in HEKswe cells. sAPP95 levels were significantly reduced in brain homogenates of 5xFAD/MT5-MMP mice, supporting altogether the idea that MT5-MMP influences APP processing. MT5-MMP emerges as a new pro-amyloidogenic regulator of APP metabolism, whose deficiency alleviates amyloid pathology, neuroinflammation and cognitive decline. [ABSTRACT FROM AUTHOR]

Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the ‘adenosine hypothesis of comorbidities’ implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic ‘comorbidity model’, in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain co-morbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions. [ABSTRACT FROM AUTHOR]

β-amyloid 1-42 (Aβ 1-42 ) is a major endogenous pathogen underlying the aetiology of Alzheimer's disease (AD). Recent evidence indicates that soluble Aβ oligomers, rather than plaques, are the major cause of synaptic dysfunction and neurodegeneration. Small molecules that suppress Aβ aggregation, reduce oligomer stability or promote off-pathway non-toxic oligomerization represent a promising alternative strategy for neuroprotection in AD. MRZ-99030 was recently identified as a dipeptide that modulates Aβ 1-42 aggregation by triggering a non-amyloidogenic aggregation pathway, thereby reducing the amount of intermediate toxic soluble oligomeric Aβ species. The present study evaluated the relevance of these promising results with MRZ-99030 under pathophysiological conditions i.e. against the synaptotoxic effects of Aβ oligomers on hippocampal long term potentiation (LTP) and two different memory tasks. Aβ 1-42 interferes with the glutamatergic system and with neuronal Ca 2+ signalling and abolishes the induction of LTP. Here we demonstrate that MRZ-99030 (100–500 nM) at a 10:1 stoichiometric excess to Aβ clearly reversed the synaptotoxic effects of Aβ 1-42 oligomers on CA1-LTP in murine hippocampal slices. Co-application of MRZ-99030 also prevented the two-fold increase in resting Ca 2+ levels in pyramidal neuron dendrites and spines triggered by Aβ 1-42 oligomers. In anaesthetized rats, pre-administration of MRZ-99030 (50 mg/kg s.c.) protected against deficits in hippocampal LTP following i.c.v. injection of oligomeric Aβ 1-42 . Furthermore, similar treatment significantly ameliorated cognitive deficits in an object recognition task and under an alternating lever cyclic ratio schedule after the i.c.v. application of Aβ 1-42 and 7PA2 conditioned medium, respectively. Altogether, these results demonstrate the potential therapeutic benefit of MRZ-99030 in AD. [ABSTRACT FROM AUTHOR]

Epidemiological studies have reported a reduction in the prevalence of Alzheimer's disease in individuals that ingest low amounts of alcohol. Also, it has been found that moderate consumption of ethanol might protect against β-amyloid (Aβ) toxicity. However, the mechanism underlying its potential neuroprotection is largely unknown. In the present study, we found that ethanol improved the cognitive processes of learning and memory in 3xTgAD mice. In addition, we found that a low concentration of ethanol (equivalent to moderate ethanol consumption) decreased the binding of Aβ (1 and 5 μM) to neuronal membranes and, consequently, its synaptotoxic effect in rat hippocampal and cortical neurons under acute (30 minutes) and chronic (24 hours) incubation conditions. This effect appears to be exerted by a direct action of ethanol on Aβ because electron microscopy studies showed that ethanol altered the degree of Aβ aggregation. The action of ethanol on Aβ also prevented the peptide from perforating the neuronal membrane, as assayed with patch clamp experiments. Taken together, these results contribute to elucidating the mechanism by which low concentrations of ethanol protect against toxicity induced by Aβ oligomers in primary neuronal cultures. These results may also provide an explanation for the decrease in the risk of Alzheimer's disease in people who consume moderate doses of alcohol. [ABSTRACT FROM AUTHOR]

Neuronal activity directly promotes the production and secretion of amyloid β (Aβ). Interestingly, neuronal hyperactivity can be observed in presymptomatic stages of both sporadic and familial Alzheimer's disease (AD) and in several AD mouse models. In this review, we will highlight the recent evidence for neuronal hyperactivity before or during the onset of cognitive defects in mild cognitive impairment. Furthermore, we review specific molecular mechanisms through which neuronal hyperactivity affects Aβ production and degradation. With these data, we will provide more insight into the 2-faced nature of neuronal hyperactivity: does enhanced neuronal activity during the presymptomatic stages of AD provide protection against the earliest disease processes or is it a pathogenic contributor to AD? [ABSTRACT FROM AUTHOR]

The neurotoxic effect of amyloid- peptide (Aβ) over the central synapses has been described and is reflected in the decrease of some postsynaptic excitatory proteins, the alteration in the number and morphology of the dendritic spines and a decrease in long- term potentiation (LTP). Many studies has been carried out to identify the putative Aβ receptors in neurons, however is still no clear why the Aβ oligomers affect only the excitatory synapse. Aβ oligomers bind to neurite and preferentially to the postsynaptic region, where the postsynaptic protein-95 (PSD-95) is present in the glutamatergic synapse. This protein through its PDZ domain interacts directly with the NMDA receptor and the adhesion protein neuroligin (NL). Neuroligin is a postsynaptic protein which binds to the presynaptic protein, neurexin (NRX) to form a heterophilic adhesion complex, involved in the establishment of pre- and postsynaptic regions. Therefore, the disruption of this interaction affects the integrity of the synaptic contact. NL-1, 3 and 4 are enriched to the excitatory synapse, while the NL-2 is found mainly in the inhibitory synapse. Structurally, NL has an extracellular domain homolog to acetylcholinesterase (AChE), the first synaptic protein that was found to interact with Aβ. In the present review we will document the interaction between Aβ and the extracellular domain of NL-1 at the excitatory synapse, as well as the interaction with other postsynaptic components, including the glutamatergic receptors (NMDA and mGluR5), prion protein, neurotrophin receptor and the 7-nicotinic acetylcholine receptor (7-nAChR). We conclude that several new Aβ oligomers receptors exist at the excitatory synapse, which could be the responsible of the neurotoxic effect described for the Aβ oligomers. The characterization of the interaction between Aβ receptors and Aβ oligomers could help to understand the source of the neurologic damage observed in the brain of the Alzheimer’s disease patients.

The mammalian target of rapamycin (mTOR) is involved in the regulation of learning and memory. Recently, rapamycin has been shown to be neuroprotective in models for Alzheimer's disease in an autophagy-dependent manner. Here we show that rapamycin exerts neuroprotection via a novel mechanism that involves presynaptic activation. Rapamycin increases the frequency of miniature excitatory postsynaptic currents and calcium transients of rat hippocampal primary neurons by a mechanism that involves the up regulation of SV2, a presynaptic vesicular protein linked to neurotransmitter release. Under these conditions, rapamycin-treated hippocampal neurons are resistant to the synaptotoxic effect induced by Aβ oligomers, suggesting that enhancers of presynaptic activity can be therapeutic agents for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract: Parkinson's disease (PD) involves an initial loss of striatal dopaminergic terminals evolving into a degeneration of dopaminergic neurons in the substantia nigra (SN), which can be modeled by 6-hydroxydopamine (6-OHDA) administration. Since ATP is a danger signal acting through its P2X7 receptors (P2X7R), we now tested if a blood-brain barrier-permeable P2X7R antagonist, Brilliant Blue G (BBG), controlled the 6-OHDA-induced PD-like features in rats. BBG (45 mg/kg) attenuated the 6-OHDA-induced: 1) increase of contralateral rotations in the apomorphine test, an effect mimicked by another P2X7R antagonist A438079 applied intra-cerebroventricularly; 2) short-term memory impairment in the passive avoidance and cued version of the Morris Water maze; 3) reduction of dopamine content in the striatum and SN; 4) microgliosis and astrogliosis in the striatum. To grasp the mechanism of action of BBG, we used in vitro models exploring synaptotoxicity (striatal synaptosomes) and neurotoxicity (dopamine-differentiated neuroblastoma SH-SY5Y cells). P2X7R were present in striatal dopaminergic terminals, and BBG (100 nM) prevented the 6-OHDA-induced synaptosomal dysfunction. P2X7R were also co-localized with tyrosine hydroxylase in SH-SY5Y cells, where BBG (100 nM) attenuated the 6-OHDA-induced neurotoxicity. This suggests that P2X7R contribute to PD pathogenesis through a triple impact on synaptotoxicity, gliosis and neurotoxicity, highlighting the therapeutic potential of P2X7R antagonists in PD. [Copyright &y& Elsevier]

Alzheimer's disease is a neurological disorder characterized by the overproduction and aggregation of amyloid-beta and the phosphorylation and intraneuronal accumulation of tau. These events promote synaptic dysfunction and loss, leading to neurodegeneration and cognitive deficits. Astrocytes are intimately associated with synapses and become activated under pathological conditions, becoming neurotoxic and detrimentally affecting synapses. Although it has been established that reducing neuronal tau expression prevents amyloid-beta-induced toxicity, the role of astrocytic tau in this setting remains understudied. Herein, we performed a series of astrocytic and neuronal primary cultures to evaluate the effects of decreasing astrocytic tau levels on astrocyte-mediated amyloid-beta-induced synaptic degeneration. Our results suggest that the downregulation of tau in astrocytes mitigates the loss of synapses triggered by their exposure to amyloid-beta. Additionally, the absence of tau from astrocytes promotes the upregulation of several synaptoprotective genes, followed by increased production of the neuroprotective factor Pentraxin 3. These results expand our understanding of the contribution of astrocytic tau to the neurodegenerative process induced by amyloid-beta-stimulation and how reducing astrocytic tau could improve astrocyte function by stimulating the expression of synaptoprotective factors. Reducing endogenous astrocytic tau expression could be a potential strategy to prevent synaptic damage in Alzheimer's disease and other neurological conditions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Not all of the mysteries of life lie in our genetic code. Some can be found buried in our membranes. These shells of fat, sculpted in the central nervous system into the cellular (and subcellular) boundaries of neurons and glia, are themselves complex systems of information. The diversity of neural phospholipids, coupled with their chameleon-like capacity to transmute into bioactive molecules, provides a vast repertoire of immediate response second messengers. The effects of compositional changes on synaptic function have only begun to be appreciated. Here, we mined 29 neurolipidomic datasets for changes in neuronal membrane phospholipid metabolism in Alzheimer's Disease (AD). Three overarching metabolic disturbances were detected. We found that an increase in the hydrolysis of platelet activating factor precursors and ethanolamine-containing plasmalogens, coupled with a failure to regenerate relatively rare alkyl-acyl and alkenyl-acyl structural phospholipids, correlated with disease severity. Accumulation of specific bioactive metabolites [i.e., PC(O-16:0/2:0) and PE(P-16:0/0:0)] was associated with aggravating tau pathology, enhancing vesicular release, and signaling neuronal loss. Finally, depletion of PI(16:0/20:4), PI(16:0/22:6), and PI(18:0/22:6) was implicated in accelerating Aβ42 biogenesis. Our analysis further suggested that converging disruptions in platelet activating factor, plasmalogen, phosphoinositol, phosphoethanolamine (PE), and docosahexaenoic acid metabolism may contribute mechanistically to catastrophic vesicular depletion, impaired receptor trafficking, and morphological dendritic deformation. Together, this analysis supports an emerging hypothesis that aberrant phospholipid metabolism may be one of multiple critical determinants required for Alzheimer disease conversion. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease is a devastating cureless neurodegenerative disorder affecting >35 million people worldwide. The disease is caused by toxic oligomers and aggregates of amyloid β protein and the microtubule-associated protein tau. Recently, the Lys-specific molecular tweezer CLR01 has been shown to inhibit aggregation and toxicity of multiple amyloidogenic proteins, including amyloid β protein and tau, by disrupting key interactions involved in the assembly process. Following up on these encouraging findings, here, we asked whether CLR01 could protect primary neurons from Alzheimer’s disease-associated synaptotoxicity and reduce Alzheimer’s disease–like pathology in vivo. Using cell culture and brain slices, we found that CLR01 effectively inhibited synaptotoxicity induced by the 42-residue isoform of amyloid β protein, including ∼80% inhibition of changes in dendritic spines density and long-term potentiation and complete inhibition of changes in basal synaptic activity. Using a radiolabelled version of the compound, we found that CLR01 crossed the mouse blood–brain barrier at ∼2% of blood levels. Treatment of 15-month-old triple-transgenic mice for 1 month with CLR01 resulted in a decrease in brain amyloid β protein aggregates, hyperphosphorylated tau and microglia load as observed by immunohistochemistry. Importantly, no signs of toxicity were observed in the treated mice, and CLR01 treatment did not affect the amyloidogenic processing of amyloid β protein precursor. Examining induction or inhibition of the cytochrome P450 metabolism system by CLR01 revealed minimal interaction. Together, these data suggest that CLR01 is safe for use at concentrations well above those showing efficacy in mice. The efficacy and toxicity results support a process-specific mechanism of action of molecular tweezers and suggest that these are promising compounds for developing disease-modifying therapy for Alzheimer’s disease and related disorders. [ABSTRACT FROM PUBLISHER]

Cdk5 dysregulation is a major event in the neurodegenerative process of Alzheimer’s disease (AD). In vitro studies using differentiated neurons exposed to Aβ exhibit Cdk5-mediated tau hyperphosphorylation, cell cycle re-entry and neuronal loss. In this study we aimed to determine the role of Cdk5 in neuronal injury occurring in an AD mouse model obtained through the intracerebroventricular (icv) injection of the Aβ1–40 synthetic peptide. In mice icv-injected with Aβ, Cdk5 activator p35 is cleaved by calpains, leading to p25 formation and Cdk5 overactivation. Subsequently, there was an increase in tau hyperphosphorylation, as well as decreased levels of synaptic markers. Cell cycle reactivation and a significant neuronal loss were also observed. These neurotoxic events in Aβ-injected mice were prevented by blocking calpain activation with , which was administered intraperitoneally (ip). As MDL prevents p35 cleavage and subsequent Cdk5 overactivation, it is likely that this kinase is involved in tau hyperphosphorylation, cell cycle re-entry, synaptic loss and neuronal death triggered by Aβ. Altogether, these data demonstrate that Cdk5 plays a pivotal role in tau phosphorylation, cell cycle induction, synaptotoxicity, and apoptotic death in postmitotic neurons exposed to Aβ peptides in vivo, acting as a link between diverse neurotoxic pathways of AD. [ABSTRACT FROM AUTHOR]

Seizures early in life cause long-term behavioral modifications, namely long-term memory deficits in experimental animals. Since caffeine and adenosine A2A receptor (A2AR) antagonists prevent memory deficits in adult animals, we now investigated if they also prevented the long-term memory deficits caused by a convulsive period early in life. Administration of kainate (KA, 2 mg/kg) to 7-days-old (P7) rats caused a single period of self-extinguishable convulsions which lead to a poorer memory performance in the Y-maze only when rats were older than 90 days, without modification of locomotion or anxiety-like behavior in the elevated-plus maze. In accordance with the relationship between synaptotoxicity and memory dysfunction, the hippocampus of these adult rats treated with kainate at P7 displayed a lower density of synaptic proteins such as SNAP-25 and syntaxin (but not synaptophysin), as well as vesicular glutamate transporters type 1 (but not vesicular GABA transporters), with no changes in PSD-95, NMDA receptor subunits (NR1, NR2A, NR2B) or α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunits (GluR1, GluR2) compared with controls. Caffeine (1 g/L) or the A2AR antagonist, KW6002 (3 mg/kg) applied in the drinking water from P21 onwards, prevented these memory deficits in P90 rats treated with KA at P7, as well as the accompanying synaptotoxicity. These results show that a single convulsive episode in early life causes a delayed memory deficit in adulthood accompanied by a glutamatergic synaptotoxicity that was prevented by caffeine or adenosine A2AR antagonists. [ABSTRACT FROM AUTHOR]

Abstract: Several studies showed that hippocampal neurons respond with an increase in synaptic transmission after chronic blockade of GABAA receptors with bicuculline, a neuroplastic phenomenon likely associated to epileptiform states. Here, we tested the effect of Aβ1–40 oligomers/aggregates, believed to be involved in Alzheimer''s Disease (AD) genesis, on this type of synaptic plasticity. In the presence of bicuculline, the frequency of miniature currents increased from 1.2±0.4 Hz to 3.1±0.6 Hz (n =6, ⁎p <0.05). Similarly, current amplitude increased from 45±3 pA to 81±11 pA (n =5, ⁎p <0.05). These effects were completely inhibited in the presence of Aβ1–40 aggregates. Data suggest that Aβ aggregates exert their influence principally by blocking synaptic transmission and altering the transcriptional pathway associated with CREB-p. In conclusion, neurons exposed to aggregated Aβ1–40 showed a reduced level of neuronal plasticity and this suggests that they might be acting as anti-epileptiform modulators. [Copyright &y& Elsevier]

Synapse loss correlates with a cognitive decline in Alzheimer's disease (AD), but whether this is caused by fibrillar deposits known as senile plaques or soluble oligomeric forms of amyloid β (Aβ) is controversial. By using array tomography, a technique that combines ultrathin sectioning of tissue with immunofluorescence, allowing precise quantification of small structures, such as synapses, we have tested the hypothesis that oligomeric Aβ surrounding plaques contributes to synapse loss in a mouse model of AD. We find that senile plaques are surrounded by a halo of oligomeric Aβ. Analysis of >14,000 synapses (represented by PSD95-stained excitatory synapses) shows that there is a 60% loss of excitatory synapses in the halo of oligomeric Aβ surrounding plaques and that the density increases to reach almost control levels in volumes further than 50 μm from a plaque in an approximately linear fashion (linear regression, r2 = 0.9; P < 0.0001). Further, in transgenic cortex, microdeposits of oligomeric Aβ associate with a subset of excitatory synapses, which are significantly smaller than those not in contact with oligomeric Aβ. The proportion of excitatory synapses associated with Aβ correlates with decreasing density (correlation, -0.588; P < 0.000 1). These data show that senile plaques are a potential reservoir of oligomeric Aβ, which colocalizes with the postsynaptic density and is associated with spine collapse, reconciling the apparently competing schools of thought of "plaque" vs. "oligomeric Aβ" as the synaptotoxic species in the brain of AD patients. [ABSTRACT FROM AUTHOR]

Abstract: Ganoderma lucidum (Leyss. ex Fr.) Karst. (Lingzhi) is a medicinal fungus used clinically in many Asian countries to promote health and longevity. Synaptic degeneration is another key mode of neurodegeneration in Alzheimer''s disease (AD). Recent studies have shown the loss of synaptic density proteins in each individual neuron during the progression of AD. It was recently reported that β-amyloid (Aβ) could cause synaptic dysfunction and contribute to AD pathology. In this study, we reported that aqueous extract of G. lucidum significantly attenuated Aβ-induced synaptotoxicity by preserving the synaptic density protein, synaptophysin. In addition, G. lucidum aqueous extract antagonized Aβ-triggered DEVD cleavage activities in a dose-dependent manner. Further studies elucidated that phosphorylation of c-Jun N-terminal kinase, c-Jun, and p38 MAP kinase was attenuated by G. lucidum in Aβ-stressed neurons. Taken together, the results prove a hypothesis that anti-aging G. lucidum can prevent harmful effects of the exterminating toxin Aβ in AD. [Copyright &y& Elsevier]

The canonical mechanism of organophosphate (OP) neurotoxicity is the inhibition of acetylcholinesterase (AChE). However, multiple lines of evidence suggest that mechanisms in addition to or other than AChE inhibition contribute to the neurotoxic effects associated with acute and chronic OP exposures. Characterizing the role(s) of AChE inhibition versus noncholinergic mechanisms in OP neurotoxicity remains an active area of research with significant diagnostic and therapeutic implications. Here, we review recently published studies that provide mechanistic insights regarding (1) OP-induced status epilepticus, (2) long-term neurologic consequences of acute OP exposures, and (3) neurotoxic effects associated with repeated low-level OP exposures. Key data gaps and challenges are also discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Among Alzheimer's disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity and the outcomes of astrocyte reactivity are far from being completely elucidated. Another key role in AD pathogenesis is played by alterations in brain cholesterol metabolism. Oxysterols (cholesterol oxidation products) are crucial for brain cholesterol homeostasis, and we previously demonstrated that changes in the brain levels of various oxysterols correlate with AD progression. Moreover, oxysterols have been shown to contribute to various pathological mechanisms involved in AD pathogenesis. In order to deepen the role of oxysterols in AD, we investigated whether they could contribute to astrocyte reactivity, and consequently impact on neuronal health. Results showed that oxysterols present in mild or severe AD brains induce a clear morphological change in mouse primary astrocytes, accompanied by the upregulation of some reactive astrocyte markers, including lipocalin-2 (Lcn2). Moreover, astrocyte conditioned media analysis revealed a significant increase in the release of Lcn2, cytokines, and chemokines in response to oxysterols. A significant reduction of postsynaptic density protein 95 (PSD95) and a concurrent increase in cleaved caspase-3 protein levels have been demonstrated in neurons co-cultured with oxysterol-treated astrocytes, pointing out that mediators released by astrocytes have an impact on neurons. Among these mediators, Lcn2 has been demonstrated to play a major role on synapses, affecting neurite morphology and decreasing dendritic spine density. These data demonstrated that oxysterols present in the AD brain promote astrocyte reactivity, determining the release of several mediators that affect neuronal health and synapses. Lcn2 has been shown to exert a key role in mediating the synaptotoxic effect of oxysterol-treated astrocytes., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Neurodegeneration is a process transversal to neuropsychiatric diseases and the understanding of its mechanisms should allow devising strategies to prevent this irreversible step in brain diseases. Neurodegeneration caused by seizures is a critical step in the aggravation of temporal lobe epilepsy, but its mechanisms remain undetermined. Convulsions trigger an elevation of extracellular adenosine and upregulate adenosine A 2A receptors (A 2A R), which have been associated with the control of neurodegenerative diseases. Using the rat and mouse kainate model of temporal lobe epilepsy, we now tested whether A 2A R control convulsions-induced hippocampal neurodegeneration. The pharmacological or genetic blockade of A 2A R did not affect kainate-induced convulsions but dampened the subsequent neurotoxicity. This neurotoxicity began with a rapid A 2A R upregulation within glutamatergic synapses (within 2 h), through local translation of synaptic A 2A R mRNA. This bolstered A 2A R-mediated facilitation of glutamate release and of long-term potentiation (LTP) in CA1 synapses (4 h), triggered a subsequent synaptotoxicity, heralded by decreased synaptic plasticity and loss of synaptic markers coupled to calpain activation (12 h), that predated overt neuronal loss (24 h). All modifications were prevented by the deletion of A 2A R selectively in forebrain neurons. This shows that synaptic A 2A R critically control synaptic excitotoxicity, which underlies the development of convulsions-induced neurodegeneration.