Explore the vast range of titles available.

Synapses between engram cells are believed to be substrates for memory storage, and the weakening or loss of these synapses leads to the forgetting of related memories. We found engulfment of synaptic components by microglia in the hippocampi of healthy adult mice. Depletion of microglia or inhibition of microglial phagocytosis prevented forgetting and the dissociation of engram cells. By introducing CD55 to inhibit complement pathways, specifically in engram cells, we further demonstrated that microglia regulated forgetting in a complement- and activity-dependent manner. Additionally, microglia were involved in both neurogenesis-related and neurogenesis-unrelated memory degradation. Together, our findings revealed complement-dependent synapse elimination by microglia as a mechanism underlying the forgetting of remote memories.

Amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer’s disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production. High nanomolar synthetic oligomeric Aβ 42 also suppresses Pr at the SC-CA1 synapse in wild-type mice. This Aβ-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP 2 ) in axons. Selectively inhibiting Aβ-induced PIP 2 hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric Aβ-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP 2 pathway whereby oligomeric Aβ induces early synaptic deficits in AD. The underlying mechanism of amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release remains unclear. Here, authors show that the release probability at the synapse between the Schaffer collateral and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production and is mainly due to an mGluR5-mediated depletion of PIP2 in axons.

Microglia continuously survey the brain parenchyma and actively shift status following stimulation. These processes demand a unique bioenergetic programme; however, little is known about the metabolic determinants in microglia. By mining large datasets and generating transgenic tools, here we show that hexokinase 2 (HK2), the most active isozyme associated with mitochondrial membrane, is selectively expressed in microglia in the brain. Genetic ablation of HK2 reduced microglial glycolytic flux and energy production, suppressed microglial repopulation, and attenuated microglial surveillance and damage-triggered migration in male mice. HK2 elevation is prominent in immune-challenged or disease-associated microglia. In ischaemic stroke models, however, HK2 deletion promoted neuroinflammation and potentiated cerebral damages. The enhanced inflammatory responses after HK2 ablation in microglia are associated with aberrant mitochondrial function and reactive oxygen species accumulation. Our study demonstrates that HK2 gates both glycolytic flux and mitochondrial activity to shape microglial functions, changes of which contribute to metabolic abnormalities and maladaptive inflammation in brain diseases. Hu et al. study the role of hexokinase 2 in microglial metabolism and function, and show its dual role under physiological and pathological conditions in a mouse model of stroke-induced neuroinflammation

Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice . Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3β binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aβ plaque of AD mice in vitro and in vivo . Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway.

Amyloid-β oligomers may cause cognitive deficits in Alzheimer’s disease by impairing neuronal NMDA-type glutamate receptors, whose function is regulated by the receptor tyrosine kinase EphB2. Here we show that amyloid-β oligomers bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer’s disease and related models, we used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centres of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation in the dentate gyrus, which are important for memory formation. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, depletion of EphB2 is critical in amyloid-β-induced neuronal dysfunction. Increasing EphB2 levels or function could be beneficial in Alzheimer’s disease. EphB2: a factor in memory loss Association studies have previously implicated the EphB2 receptor in Alzheimer's disease. As a member of a large family of tyrosine kinase receptors that regulate diverse biological functions, its role in the condition remained unknown. Cissé et al . now show that amyloid-β oligomers interact with EphB2 and trigger its degradation. EphB2 regulates NMDA-type glutamate receptors, and its depletion in normal mice reduces NMDAR currents and impairs long-term potentiation, both of which are important for memory formation. Increasing EphB2 levels in a mouse model of Alzheimer's disease improves memory, suggesting that increasing EphB2 levels or function could be of therapeutic value in Alzheimer's disease. It is shown that amyloid-β oligomers interact with the receptor tyrosine kinase EphB2 and trigger its degradation. EphB2 regulates NMDA-type glutamate receptors and its depletion in normal mice reduces NMDA receptor currents and impairs long-term potentiation, both of which are important for memory formation. Increasing EphB2 levels in a mouse model of Alzheimer's disease improves memory.

Background Abnormal excitability of hippocampal neurons may lead to dysfunction of neural circuits and then causes cognitive impairments in Alzheimer’s disease (AD). However, the underlying mechanisms remain to be fully elucidated. Methods Electrophysiology was performed to examine the intrinsic excitability of CA1 neurons and the activity of the hyperpolarization-activated cyclic nucleotide-gated ion channels (HCNs) of CA1 neurons in wild type (WT) and hAPP-J20 mice. The activity of CA1 pyramidal neurons (PNs) was modulated with chemogenetics. The activity of HCNs was regulated with nonselective facilitator (cAMP) or inhibitor (ZD7288) of HCNs. Immunohistochemical staining or western blotting were performed to examine the expression of HCN1 and HCN2 in the hippocampus of WT and hAPP-J20 mice, or AD patients and non-AD controls. AAVs were injected to specifically modulate the expression of HCN2 in dorsal CA1 (dCA1) PNs. Cognitive performance of mice was assessed with behavioral tests. Results dCA1 PNs were more excitable in hAPP-J20 mice, but the excitability of PNs in the ventral CA1 (vCA1) or PV neurons was comparable between WT and hAPP-J20 mice. The activity of the HCNs was reduced in dCA1 PNs of hAPP-J20 mice, and pharmacologically increasing the activity of HCNs attenuated the hyperexcitability of dCA1 PNs in hAPP-J20 mice, suggesting that the reduced activity of HCNs is associated with the hyperexcitability of dCA1 PNs in hAPP-J20 mice. The expression of HCN2 but not HCN1 was reduced in the hippocampus of hAPP-J20 mice, and the expression of HCN2 was also reduced in the hippocampus of AD patients, suggesting that dysregulation of HCN2 is associated with the reduced activity of HCNs in AD. Overexpressing HCN2 rescued the activity of HCNs, attenuated the hyperexcitability of dCA1 PNs and improved memory of hAPP-J20 mice, and knocking down HCN2 impaired the function of HCNs, increased the excitability of dCA1 PNs and led to memory deficits in WT mice. Conclusions Our data suggest that dysregulation of HCNs, particularly HCN2, contributes to the abnormal excitability of CA1 PNs in AD mice and probably in AD patients as well, and thus provide new insights into the mechanisms underlying the aberrant activity or excitability of hippocampal neurons in AD.

GFAP-TK mice are widely used in studies on neurogenesis and reactive astrocytes. Previous studies reported that GCV treatment in GFAP-TK mice resulted in reduced neurogenesis and deletion of proliferating GFAP-expressing astrocytes without affecting mature GFAP-expressing astrocytes. In the present study, we found that GFAP- and vimentin-expressing astrocytes were dramatically increased in the cortex and hippocampus with or without GCV treatment in a line of GFAP-TK mice (Jackson Laboratory, Stock No. 005698), while the neurons and microglia were not affected. In a second line of GFAP-TK mice (MMRRC, Stock No. 037351-UNC) generated in Dr. Heather Cameron's laboratory in NIH, however, no difference in GFAP and vimentin expression was found in both hippocampus and cortex, regardless of GCV treatment or not. Furthermore, enhanced expression of aquaporin 4 (AQP4) was found in the cortex and hippocampus of the GFAP-TK mice from Jackson lab but not in the brain of GFAP-TK mice from NIH. Our data suggested that we should be careful to select different lines of GFAP-TK mice to study adult neurogenesis or reactive astrocytes.

Pharmacological therapies to treat Alzheimer's disease (AD) targeting “Aβ” have failed for over 100 years. Low levels of laser light can disassemble Aβ. In this study, we investigated the mechanisms that Aβ-blocked extracellular space (ECS) induces memory disorders in APP/PS1 transgenic mice and addressed whether red light (RL) at 630 nm rescues cognitive decline by reducing Aβ-disturbed flow of interstitial fluid (ISF). We compared the heating effects on the brains of rats illuminated with laser light at 630, 680, and 810 nm for 40 minutes, respectively. Then, a light-emitting diode with red light at 630 nm (LED-RL) was selected to illuminate AD mice. The changes in the structure of ECS in the cortex were examined by fluorescent double labeling. The volumes of ECS and flow speed of ISF were quantified by magnetic resonance imaging. Spatial memory behaviors in mice were evaluated by the Morris water maze. Then, the brains were sampled for biochemical analysis. RL at 630 nm had the least heating effects than other wavelengths associated with ~49% penetration ratio into the brains. For the molecular mechanisms, Aβ could induce formaldehyde (FA) accumulation by inactivating FA dehydrogenase. Unexpectedly, in turn, FA accelerated Aβ deposition in the ECS. However, LED-RL treatment not only directly destroyed Aβ assembly in vitro and in vivo but also activated FA dehydrogenase to degrade FA and attenuated FA-facilitated Aβ aggregation. Subsequently, LED-RL markedly smashed Aβ deposition in the ECS, recovered the flow of ISF, and rescued cognitive functions in AD mice. Aβ-obstructed ISF flow is the direct reason for the failure of the developed medicine delivery from superficial into the deep brain in the treatment of AD. The phototherapy of LED-RL improves memory by reducing Aβ-blocked ECS and suggests that it is a promising noninvasive approach to treat AD. [Display omitted] •Aβ-inactivated formaldehyde dehydrogenase induces formaldehyde accumulation.•Formaldehyde in turn accelerates Aβ deposition in the extracellular space.•Red light activates formaldehyde dehydrogenase to degrade formaldehyde.•Red light reduces Aβ self-aggregation and formaldehyde-promoted assembly.•Red light recovers interstitial fluid flow and alleviates memory deficits.

Background Microglia, the resident immune cells of the brain, have been implicated in brain injury and various neurological disorders. However, their precise roles in different pathophysiological situations remain enigmatic and may range from detrimental to protective. Targeting the delivery of biologically active compounds to microglia could help elucidate these roles and facilitate the therapeutic modulation of microglial functions in neurological diseases. Methods Here we employ primary cell cultures and stereotaxic injections into mouse brain to investigate the cell type specific localization of semiconductor quantum dots (QDs) in vitro and in vivo. Two potential receptors for QDs are identified using pharmacological inhibitors and neutralizing antibodies. Results In mixed primary cortical cultures, QDs were selectively taken up by microglia; this uptake was decreased by inhibitors of clathrin-dependent endocytosis, implicating the endosomal pathway as the major route of entry for QDs into microglia. Furthermore, inhibiting mannose receptors and macrophage scavenger receptors blocked the uptake of QDs by microglia, indicating that QD uptake occurs through microglia-specific receptor endocytosis. When injected into the brain, QDs were taken up primarily by microglia and with high efficiency. In primary cortical cultures, QDs conjugated to the toxin saporin depleted microglia in mixed primary cortical cultures, protecting neurons in these cultures against amyloid beta-induced neurotoxicity. Conclusions These findings demonstrate that QDs can be used to specifically label and modulate microglia in primary cortical cultures and in brain and may allow for the selective delivery of therapeutic agents to these cells.