Astrocyte-to-neuron H2O2 signalling supports long-term memory formation in Drosophila and is impaired in an Alzheimer’s disease model

Nature Metabolism, Год журнала: 2025, Номер unknown

Опубликована: Янв. 24, 2025

Abstract Astrocytes help protect neurons from potential damage caused by reactive oxygen species (ROS). While ROS can also exert beneficial effects, it remains unknown how neuronal signalling is activated during memory formation, and whether astrocytes play a role in this process. Here we discover an astrocyte-to-neuron H 2 O cascade Drosophila that essential for long-term formation. Stimulation of acetylcholine induces increase intracellular calcium ions, which triggers the generation extracellular superoxide (O • – ) astrocytic NADPH oxidase. Astrocyte-secreted dismutase 3 (Sod3) converts to hydrogen peroxide (H ), imported into olfactory centre, mushroom body, as revealed vivo imaging. Notably, Sod3 activity requires copper are supplied amyloid precursor protein. We find human amyloid-β peptide, implicated Alzheimer’s disease, inhibits nAChRα7 cholinergic receptor impairs formation preventing synthesis. These findings may have important implications understanding aetiology disease.

Язык: Английский

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Alzheimer's therapeutics: Continued clinical failures question the validity of the amyloid hypothesis—but what lies beyond?

Biochemical Pharmacology, Год журнала: 2012, Номер 85(3), С. 289 - 305

Опубликована: Ноя. 22, 2012

Язык: Английский

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Deciphering Alzheimer Disease

Cold Spring Harbor Perspectives in Medicine, Год журнала: 2011, Номер 2(1), С. a011460 - a011460

Опубликована: Окт. 25, 2011

Alzheimer disease represents an insidious impairment of intellect and emotional well-being. However, recent advances in biochemical pathology human genetics offer promise that effective therapeutic agents may soon be developed.

Язык: Английский

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Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity

Acta Neuropathologica, Год журнала: 2014, Номер 129(1), С. 21 - 37

Опубликована: Ноя. 29, 2014

Язык: Английский

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AP-4 mediates export of ATG9A from thetrans-Golgi network to promote autophagosome formation

Proceedings of the National Academy of Sciences, Год журнала: 2017, Номер 114(50)

Опубликована: Ноя. 27, 2017

AP-4 is a member of the heterotetrameric adaptor protein (AP) complex family involved in sorting endomembrane system eukaryotic cells. Interest has recently risen with discovery that mutations any its four subunits cause form hereditary spastic paraplegia (HSP) intellectual disability. The critical events mediated by and pathogenesis deficiency, however, remain poorly understood. Here we report identification ATG9A, only multispanning membrane component core autophagy machinery, as specific cargo. promotes signal-mediated export ATG9A from trans-Golgi network to peripheral cytoplasm, contributing lipidation LC3B maturation preautophagosomal structures. These findings implicate regulator altered possible defect AP-4-deficient HSP.

Язык: Английский

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LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent

eLife, Год журнала: 2017, Номер 6

Опубликована: Июль 11, 2017

The concurrent application of subtoxic doses soluble oligomeric forms human amyloid-beta (oAβ) and Tau (oTau) proteins impairs memory its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued these findings, we investigated whether oAβ oTau share a common mechanism when they impair LTP in mice. We found as already shown for oAβ, also can bind to amyloid precursor protein (APP). Moreover, efficient uptake requires expression APP. Finally, the toxic effect both extracellular on is dependent upon APP since APP-KO mice were resistant oAβ- oTau-induced defects spatial/associative LTP. Thus, might serve therapeutic target against Alzheimer's Disease (AD) host other neurodegenerative diseases characterized abnormal levels Aβ and/or Tau.

Язык: Английский

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Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP

Journal of Neuroscience, Год журнала: 2017, Номер 37(49), С. 11947 - 11966

Опубликована: Ноя. 3, 2017

Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD) and several theories have been advanced explain relationship. A leading hypothesis proposes that a small amphipathic fragment of APP, β-protein (Aβ), self-associates form soluble aggregates impair synaptic network activity. Here, we used most disease-relevant Aβ, isolated from AD brain. Using this material, show synaptotoxic effects Aβ depend on expression APP Aβ-mediated impairment plasticity is accompanied by presynaptic disrupt excitatory/inhibitory (E/I) balance. The net increase in E/I ratio inhibition are associated with localizing synapses binding requires APP. Our findings indicate role for pathogenesis beyond generation suggest modulation as therapy AD. SIGNIFICANCE STATEMENT report plasticity-disrupting (Aβ) brain requirement these effects. We Aβ-containing extracts block hippocampal LTP, augment glutamate release probability, These ablation prevents both dysfunctions. results emphasize importance should stimulate new studies elucidate APP-related targets suitable pharmacological manipulation.

Язык: Английский

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Amyloid Precursor Protein Dimerization and Synaptogenic Function Depend on Copper Binding to the Growth Factor-Like Domain

Journal of Neuroscience, Год журнала: 2014, Номер 34(33), С. 11159 - 11172

Опубликована: Авг. 13, 2014

Accumulating evidence suggests that the copper-binding amyloid precursor protein (APP) has an essential synaptic function. APP synaptogenic function depends on trans-directed dimerization of extracellular E1 domain encompassing a growth factor-like (GFLD) and (CuBD). Here we report 1.75 Å crystal structure GFLD in complex with copper ion bound high affinity to extended hairpin loop at interface. In coimmunoprecipitation assays binding promotes interaction, whereas mutations sites either or CuBD result drastic reduction cis-orientated dimerization. We show is sufficient induce purified APP. Furthermore, mixed culture assay primary neurons HEK293 cells expressing different mutants revealed potently synaptogenesis depending GFLD. Together, these findings demonstrate required for cis-/trans-directed Thus, neuronal activity disease-associated changes homeostasis likely go along altered

Язык: Английский

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The Role of Immunosenescence in Neurodegenerative Diseases

Mediators of Inflammation, Год журнала: 2018, Номер 2018, С. 1 - 12

Опубликована: Янв. 1, 2018

Aging is characterized by the progressive decline of physiological function and tissue homeostasis leading to increased vulnerability, degeneration, death. Aging-related changes innate adaptive immune system include in preservation enhancement many functions, such as number circulating monocytic dendritic cells, thymic involution, T cell polyfunctionality, or production proinflammatory cytokines, are defined immunosenescence. Inflammatory functions with age, causing chronic low-grade inflammation, referred inflamm-aging, that contribute, together immunosenescence, neurodegenerative diseases. In this review, we discuss link between nervous systems how immunosenescence inflamm-aging can contribute

Язык: Английский

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The keystone of Alzheimer pathogenesis might be sought in Aβ physiology

Neuroscience, Год журнала: 2015, Номер 307, С. 26 - 36

Опубликована: Авг. 24, 2015

Язык: Английский

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