Neuronal Homeostasis Research Articles

Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer’s disease

Early Alzheimer’s disease (AD) is associated with hippocampal hyperactivity and decreased sleep quality. Here we show that homeostatic mechanisms transiently counteract the increased excitatory drive to CA1 neurons in AppNL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in AppNL-G-F mice. Pmch encodes melanin-concentrating hormone (MCH), which is produced in sleep–active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission, modulates firing rate homeostasis in hippocampal neurons and reverses the increased excitatory drive to CA1 neurons in AppNL-G-F mice. AppNL-G-F mice spend less time in rapid eye movement (REM) sleep. AppNL-G-F mice and individuals with AD show progressive changes in morphology of CA1-projecting MCH axons. Our findings identify the MCH system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampus-dependent functions.

Influence of Auditory Integrative Training on Casein Kinase 2 and Its Impact on Behavioral and Social Interaction in Children with Autism Spectrum Disorder

Considerable disturbances in post-translational protein phosphorylation have recently been discovered in multiple neurological disorders. Casein kinase-2 (CK2) is a tetrameric Ser/Thr protein kinase that phosphorylates a large number of substrates and contributes in several cellular physiological and pathological processes. CK2 is highly expressed in the mammalian brain and catalyzes the phosphorylation of a large number of substrates that are crucial in neuronal or glial homeostasis and inflammatory signaling processes across synapses. In this study, we investigated the impact of auditory integration therapy (AIT) for the treatment of sensory processing abnormalities in autism on plasma CK2 levels. A total of 25 ASD children, aged between 5 and 12 years, were enrolled and participated in the present research study. AIT was performed for two weeks, for a period of 30 min, twice a day, with a 3 h interval between sessions. Before and after AIT, the Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Short Sensory Profile (SSP) scores were calculated, and plasma CK2 levels were assayed using an ELISA test. The CARS and SRS indices of autism severity improved as a result of AIT, which could be related to the decreased level of plasma CK2. However, the mean value of the SSP scores was not significantly increased after AIT. The relationship between CK2 downregulation and glutamate excitotoxicity, neuro-inflammation, and leaky gut, as etiological mechanisms in ASD, was proposed and discussed. Further research, conducted on a larger scale and with a longer study duration, are required to assess whether the cognitive improvement in ASD children after AIT is related to the downregulation of CK2.

Protocol of a Phase II Randomized, Multi-Center, Double-Blind, Placebo-Controlled Trial of S-Adenosyl Methionine in Participants with Mild Cognitive Impairment or Dementia Due to Alzheimer’s Disease

BackgroundS-adenosyl methionine (SAMe) is a pivotal metabolite in multiple pathways required for neuronal homeostasis, several of which are compromised in Alzheimer’s disease (AD). Correction of the SAMe deficiency that is characteristic of the AD brain may attenuate or prevent pathological processes driving AD-associated neurodegeneration including aberrant tau hyperphosphorylation and DNA hypomethylation.ObjectivesThe primary aim is to test the hypothesis that daily treatment with 400 mg oral SAMe for 180 days will lead to a greater reduction from baseline in plasma levels of p-tau181 compared to placebo in patients with mild cognitive impairment or dementia due to AD.Design, Setting, ParticipantsThis is a phase II, randomized, multi-center, double-blind, placebo-controlled trial among 60 participants with mild cognitive impairment or dementia due to AD. Participants will be randomized in a 1:1 ratio to receive either SAMe or matching placebo, to be taken as an adjunct to their AD standard of care.Measurements and ResultsThe primary outcome is change in plasma p-tau181 concentration between baseline and following 180 days of treatment, which will be compared between the active and placebo group. Secondary outcomes are the safety of SAMe administration (incidence of serious adverse events), change from baseline in cognitive performance (as measured by the Repeatable Battery for the Assessment of Neuropsychological Status), and epigenetic changes in DNA methylation.ConclusionDemonstration of effective and safe lowering of plasma p-tau181 with SAMe in this phase II trial would pave the way for an exciting field of translational research and a larger phase III trial.

Measurement of solute permeability in the mouse spinal cord

BackgroundSensory perception and motor dexterity is coordinated by the spinal cord, which remains effective due to maintenance of neuronal homeostasis. This is stringently controlled by the blood spinal cord barrier. Therefore, the function of the spinal cord is susceptible to alterations in the microvessel integrity (e.g. vascular leakage) and/or perfusion (e.g. changes in blood flow). New MethodSpinal cord solute permeability was measured in anaesthetised mice. The lumbar spinal cord vertebra were stabilised and a coverslip secured to allow fluorescent tracers of vascular function and anatomy to be visualised in the vascular network. Fluorescence microscopy allowed real time measurements of vascular leakage and capillary perfusion within the spinal cord. ResultsCapillaries were identified through fluorescent labelling of the endothelial luminal glycocalyx (wheat germ agglutin 555). Real time estimation of vascular permeability through visualisation of sodium fluorescein transport was recorded from identified microvessels in the lumbar dorsal horn of the spinal cord. Comparison with existing method(s)Current approaches have used histological and/or tracer based in-vivo assays alongside cell culture to determine endothelium integrity and/or function. These only provide a snapshot of the developing vasculopathy, restricting the understanding of physiological function or disease progression over time. ConclusionsThese techniques allow for direct visualisation of cellular and/or mechanistic influences upon vascular function and integrity, which can be applied to rodent models including disease, transgenic and/or viral approaches. This combination of attributes allows for real time understanding of the function of the vascular network within the spinal cord.

Neuro death through autophagy via the acetylation of FoxO1 by SIRT2 in the hippocampus of mice in a autism spectrum disorder mice model.

Autism Spectrum Disorder (ASD) is a series of complex neurodevelopmental disorders, which can affect children's social, behavioral and communication abilities. A member of the Sirtuins family of NAD+dependent deacetylases called SIRT2 could regulate the inflammation progress during stress, but the relevant mechanism has not been clearly defined. In the present study, the ASD model of wild type and SIRT2 knock out mice was established to evaluate the impact on the homeostasis of neurons in the hippocampus using western blotting, immunofluorescence and Nissl staining. The results showed that the amplification of neuronal richness was significantly decreased and neuroinflammation increased in the hippocampus following ASD due to autophagy, caused by enhancing the acetylation of FoxO1 using SIRT2 gene deletion and indicating this should be the target for ASD or other psychological stress treatment. This article is protected by copyright. All rights reserved.

Cigarette smoke triggers calcium overload in mouse hippocampal neurons via the ΔFOSB-CACNA2D1 axis to impair cognitive performance

A growing body of evidence shows that cigarette smoking impairs cognitive performance. The 'Calcium Hypothesis' theory of neuronopathies reveals a critical role of aberrant calcium signaling in compromised cognitive functions. However, the underlying implications of abnormalities in calcium signaling in the neurotoxicity induced by cigarette smoke (CS) have not yet been identified. CACNA2D1, an important auxiliary subunit involved in the composition of voltage-gated calcium channels (VGCCs), was reported to affect the calcium signaling in neurons by facilitating VGCCs-mediated Ca2+ influx. ΔFOSB, an alternatively-spliced product of the Fosb gene, is an activity-dependent transcription factor induced robustly in the brain in response to environmental stimuli such as CS. Interestingly, our preliminary bioinformatics analysis revealed a significant co-expression between ΔFOSB and CACNA2D1 in brain tissues of patients with neurodegenerative diseases characterized by progressive cognitive decline. Therefore, we hypothesized that the activation of the ΔFOSB-CACNA2D1 axis in response to CS exposure might cause dysregulation of calcium homeostasis in hippocampal neurons via VGCCs-mediated Ca2+ influx, thereby contributing to cognitive deficits. To this end, the present study established a CS-induced mouse model of hippocampus-dependent cognitive impairment, in which the activation of the ΔFOSB-CACNA2D1 axis accompanied by severe calcium overload was observed in the mouse hippocampal tissues. More importantly, ΔFOSB knockdown-/overexpression-mediated inactivation/activation of the ΔFOSB-CACNA2D1 axis interdicted/mimicked CS-induced dysregulation of calcium homeostasis followed by severe cellular damage in HT22 mouse hippocampal neurons. Mechanistically speaking, a further ChIP-qPCR assay confirmed the physical interaction between transcription factor ΔFOSB and the Cacna2d1 gene promoter, suggesting a direct transcriptional regulation of the Cacna2d1 gene by ΔFOSB. Overall, our current work aims to deliver a unique insight into the neurotoxic mechanisms induced by CS to explore potential targets for intervention.

Speech- and language-linked FOXP2 mutation targets protein motors in striatal neurons.

Human speech and language are among the most complex motor and cognitive abilities. The discovery of a mutation in the transcription factor FOXP2 in KE family members with speech disturbances has been a landmark example of the genetic control of vocal communication in humans. Cellular mechanisms underlying this control have remained unclear. By leveraging FOXP2 mutation/deletion mouse models, we found that the KE family FOXP2R553H mutation directly disables intracellular dynein-dynactin 'protein motors' in the striatum by induction of a disruptive high level of dynactin1 that impairs TrkB endosome trafficking, microtubule dynamics, dendritic outgrowth and electrophysiological activity in striatal neurons alongside vocalization deficits. Dynactin1 knockdown in mice carrying FOXP2R553H mutations rescued these cellular abnormalities and improved vocalization. We suggest that FOXP2 controls vocal circuit formation by regulating protein motor homeostasis in striatal neurons, and that its disruption could contribute to the pathophysiology of FOXP2 mutation/deletion-associated speech disorders.

The role of RPTPz in neuronal intracellular pH homeostasis and in crosstalk to adjacent astrocytes

Receptor protein tyrosine phosphatase ζ (RPTPζ) is a transmembrane protein almost exclusively expressed in the CNS regulates cells adhesion and signaling during development. RPTPζ ‘s close homolog RPTPγ, senses extracellular CO₂/HCO₃⁻ and modulates acid-base transport in response to basolateral Δ[CO₂] and Δ[HCO₃⁻] in the kidney. Here, we investigate if RPTPζ similarly defends against acid-base disturbances in the brain. We hypothesize that metabolic (MAc) or respiratory (RAc) acidosis ↑RPTPζ phosphatase activity to regulate the signal cascades that defend cells against intracellular pH (pHi) decreases. ↑[CO₂]ₒ or ↓[HCO₃⁻]ₒ that stimulate RPTPζ phosphatase activity could ↑acid-extrusion or ↓acid-loading rates, both of which would minimize the ↓pHi during MAc or RAc, and may promote adaptation during a subsequent acidosis. RT-PCR cloning from co-cultures of mouse hippocampal (HC) neurons and astrocytes, and pup or adult mouse HC tissue identifies six expressed RPTPζ variants. Three previously validated variants: NM_001081306, NM_001311064, and NM_001361349 and three variants formerly identified as hypothetical assemblies: XM_006505013, XM_006505014, and XM_006505015. Staining in HC co-cultures and pup or adult HC tissue sections determined that RPTPζ exclusively expresses in MAP2-positive neurons and not GFAP-positive astrocytes. pH-sensitive microfluorimetry on HC co-cultures subject to dual RAc (8% CO₂/22 mM HCO₃⁻) or MAc (5% CO₂/14 mM HCO₃⁻) pulses show wild-type (WT) neurons exhibit consistent baseline pHi ((pHi)Ctrl) values when perfused with 5% CO₂/22 mM HCO₃⁻ (pH 7.4) buffer compared to RPTPζ–/– neurons that exhibit more variable and more acidic mean (pHi)Ctrl. Moreover, in response to RAc, RPTPζ–/– neurons exhibit slower maximum rates of acidification ((dpHi/dt)early) during the first RAc, and larger ΔpHi during both RAc pulses compared to WT. In response to dual MAc, pulses, RPTPζ–/– neurons exhibit faster (dpHi/dt)early during both MAc pulses compared to WT neurons, and faster (dpHi/dt)2early vs. (dpHi/dt)1early. MAc-induced (dpHi/dt)1early = (dpHi/dt)2early in WT neurons. ΔpHi is larger in RPTPζ–/– vs. WT neurons during both MAc pulses, but is not different between Δ(pHi)1 vs. Δ(pHi)2. RPTPζ–/– astrocytes exhibit more acidic (pHi)Ctrl values, larger ΔpHi and slower (dpHi/dt)early during both RAc pulses vs. WT, with no change in acidification rate between the first and second RAc pulse. MAc-exposed RPTPζ –/– astrocytes do not exhibit substantially greater ΔpHi vs. WT astrocytes, but do present faster (dpHi/dt)early during both MAc pulses. Our data indicate that both RPTPζ –/– HC neurons and astrocytes are less able to defend against RAc or MAc compared to WT. However, because we do not detect RPTPζ –/– expression in astrocytes our results highlight a potential RPTPζ –/–-mediated neuron–astrocyte crosstalk that modulates acid extrusion in the astrocytes. R01-DK113197, DK128315 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hypothalamic PVN astrocytes fail to properly set glutamate tone in obese mice contributing to impaired glucose metabolism in this condition

The hypothalamus is key in the control of energy balance, but strategies targeting hypothalamic neurons have failed to provide viable options to treat most metabolic diseases. Conversely, the role of astrocytes in systemic metabolic control has remained largely unexplored. Here, we show that obesity promotes anatomically restricted exacerbated Ca 2+ activity in hypothalamic paraventricular nucleus (PVN) astrocytes. Bidirectional chemogenetic manipulation of astrocyte Ca 2+ activity in lean mice stimulated or inhibited the activity of neighboring parvocellular neurons. Importantly, these effects translated into bidirectional regulation of sympathetic activity, glucose metabolism, and energy balance. We found that the astrocyte-mediated effects on PVN neurons were blocked by the glutamate receptor blocker kynurenic acid, and the astrocyte glutamate transport blocker TBOA, suggesting that the astrocyte-neuron signaling and the effects on glucose metabolism involved the astrocytic control of ambient glutamate levels. Notably, we found that TBOA alone stimulated neurons in lean mice but failed to evoke a response in obese mice. This suggests that the astrocyte glutamate transporter activity is impaired in obese mice. Finally, we found that chemogenetic inhibition of astrocyte Ca 2+ activity in obese mice improved glucose metabolism in this condition. Together, our results indicate that exacerbated astrocyte Ca 2+ activity leads to impaired glutamate transporter activity, standing as a likely mechanism contributing to altered PVN neuronal activity and glucose homeostasis during this condition. Collectively, these findings highlight a yet unappreciated role for astrocytes in the direct control of systemic metabolism and suggest potential targets for anti-obesity strategy. NHLBI F32 HL158172 (MKK) NHLBI HL090948 (JES) NINDS NS094640 (JES) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impaired Cholesterol Metabolism, Neurons, and Neuropsychiatric Disorders

Cholesterol metabolism plays an essential role in cellular functions (including as a component of the plasma membrane, as an energy source, and in hormone production) under normal conditions. Dysregulated cholesterol metabolism causes a wide spectrum of pathological conditions, leading to neuropsychiatric disorders, such as anxiety and depression. In addition, patients with neuropsychiatric disorders also have impaired cholesterol metabolism. Therefore, metabolic disturbances are closely associated with the neuropsychiatric disorders. Although immune disturbance, neuroinflammation, a dysregulated neurotransmitter system, and oxidative stress have been suggested as pathophysiology of neuropsychiatric disorders, dysregulation of cholesterol metabolism is also found in patients with psychiatric diseases. As expected, patients with mental illness appear to be at risk of metabolic disorders, including metabolic syndrome, in which cholesterol influences altered neuronal homeostasis, such as neuronal cell toxicity, neuronal cell death, and neuronal structures and functions, including synaptogenesis, neurogenesis, axonogenesis, and action potential. Therefore, reversing impaired or abnormal cholesterol metabolism may help restore neuronal injury found in mental illness. This review is aimed to discuss the links between cholesterol metabolism impairment and neuropsychiatric disorders and provides insights into neuronal dysfunction due to abnormal cholesterol metabolism in neuropsychiatric disorders.

Role of microglia autophagy and mitophagy in age-related neurodegenerative diseases.

Microglia, characterized by responding to damage, regulating the secretion of soluble inflammatory mediators, and engulfing specific segments in the central nervous system (CNS), function as key immune cells in the CNS. Emerging evidence suggests that microglia coordinate the inflammatory responses in CNS system and play a pivotal role in the pathogenesis of age-related neurodegenerative diseases (NDDs). Remarkably, microglia autophagy participates in the regulation of subcellular substances, which includes the degradation of misfolded proteins and other harmful constituents produced by neurons. Therefore, microglia autophagy regulates neuronal homeostasis maintenance and process of neuroinflammation. In this review, we aimed at highlighting the pivotal role of microglia autophagy in the pathogenesis of age-related NDDs. Besides the mechanistic process and the co-interaction between microglia autophagy and different kinds of NDDs, we also emphasized potential therapeutic agents and approaches that could be utilized at the onset and progression of these diseases through modulating microglia autophagy, including promising nanomedicines. Our review provides a valuable reference for subsequent studies focusing on treatments of neurodegenerative disorders. The exploration of microglia autophagy and the development of nanomedicines greatly enhances current understanding of NDDs.

The Translocase of the Outer Mitochondrial Membrane (TOM40) is required for mitochondrial dynamics and neuronal integrity in Dorsal Root Ganglion Neurons

Polymorphisms and altered expression of the Translocase of the Outer Mitochondrial Membrane – 40 kD (Tom40) are observed in neurodegenerative disease subjects. We utilized in vitro cultured dorsal root ganglion (DRG) neurons to investigate the association of TOM40 depletion to neurodegeneration, and to unravel the mechanism of neurodegeneration induced by decreased levels of TOM40 protein. We provide evidence that severity of neurodegeneration induced in the TOM40 depleted neurons increases with the increase in the depletion of TOM40 and is exacerbated by an increase in the duration of TOM40 depletion. We also demonstrate that TOM40 depletion causes a surge in neuronal calcium levels, decreases mitochondrial motility, increases mitochondrial fission, and decreases neuronal ATP levels. We observed that alterations in the neuronal calcium homeostasis and mitochondrial dynamics precede BCL-xl and NMNAT1 dependent neurodegenerative pathways in the TOM40 depleted neurons. This data also suggests that manipulation of BCL-xl and NMNAT1 may be of therapeutic value in TOM40 associated neurodegenerative disorders.

The proteasome: A key modulator of nervous system function, brain aging, and neurodegenerative disease.

The proteasome is a large multi-subunit protease responsible for the degradation and removal of oxidized, misfolded, and polyubiquitinated proteins. The proteasome plays critical roles in nervous system processes. This includes maintenance of cellular homeostasis in neurons. It also includes roles in long-term potentiation via modulation of CREB signaling. The proteasome also possesses roles in promoting dendritic spine growth driven by proteasome localization to the dendritic spines in an NMDA/CaMKIIα dependent manner. Proteasome inhibition experiments in varied organisms has been shown to impact memory, consolidation, recollection and extinction. The proteasome has been further shown to impact circadian rhythm through modulation of a range of 'clock' genes, and glial function. Proteasome function is impaired as a consequence both of aging and neurodegenerative diseases. Many studies have demonstrated an impairment in 26S proteasome function in the brain and other tissues as a consequence of age, driven by a disassembly of 26S proteasome in favor of 20S proteasome. Some studies also show proteasome augmentation to correct age-related deficits. In amyotrophic lateral sclerosis Alzheimer's, Parkinson's and Huntington's disease proteasome function is impaired through distinct mechanisms with impacts on disease susceptibility and progression. Age and neurodegenerative-related deficits in the function of the constitutive proteasome are often also accompanied by an increase in an alternative form of proteasome called the immunoproteasome. This article discusses the critical role of the proteasome in the nervous system. We then describe how proteasome dysfunction contributes to brain aging and neurodegenerative disease.

An Overview of the Putative Structural and Functional Properties of the GHBh1 Receptor through a Bioinformatics Approach.

The neurotransmitter γ-hydroxybutyric acid (GHB) is suggested to be involved in neuronal energy homeostasis processes, but the substance is also used as a recreational drug and as a prescription medication for narcolepsy. GHB has several high-affinity targets in the brain, commonly generalized as the GHB receptor. However, little is known about the structural and functional properties of GHB receptor subtypes. This opinion article discusses the literature on the putative structural and functional properties of the GHBh1 receptor subtype. GHBh1 contains 11 transmembrane helices and at least one intracellular intrinsically disordered region (IDR). Additionally, GHBh1 shows a 100% overlap in amino acid sequence with the Riboflavin (vitamin B2) transporter, which opens the possibility of a possible dual-function (transceptor) structure. Riboflavin and GHB also share specific neuroprotective properties. Further research into the GHBh1 receptor subtype may pave the way for future therapeutic possibilities for GHB.

The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases.

Mitochondrial dysfunction and vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases. It has become clear that pathogenetic pathways leading to neurodegeneration are often interconnected. Indeed, growing evidence suggests a concerted contribution of impaired mitophagy and vesicles formation in the dysregulation of neuronal homeostasis, contributing to neuronal cell death. Among the molecular factors involved in the trafficking of vesicles, Ras analog in brain (Rab) proteins seem to play a central role in mitochondrial quality checking and disposal through both canonical PINK1/Parkin-mediated mitophagy and novel alternative pathways. In turn, the lack of proper elimination of dysfunctional mitochondria has emerged as a possible causative/early event in some neurodegenerative diseases. Here, we provide an overview of major findings in recent years highlighting the role of Rab proteins in dysfunctional mitochondrial dynamics and mitophagy, which are characteristic of neurodegenerative diseases. A further effort should be made in the coming years to clarify the sequential order of events and the molecular factors involved in the different processes. A clear cause-effect view of the pathogenetic pathways may help in understanding the molecular basis of neurodegeneration.

TRP Channels as Emerging Therapeutic Targets in Neurological Disorders

Neurological disorders like Parkinson disease (PD), Alzheimer’s disease (AD), epilepsy, stroke, schizophrenia, depression, bipolar disorder, etc., are increasingly recognized as signifi cant causes of death and disability globally. All these neurological disorders have several similar causes, such as disturbance in Ca2+ homeostasis and misfolded proteins deposition in the brain through impairing the function of a no. of ion channels, including TRP channels. TRP channels superfamily consists of a broad collection of non-selective Ca2+ permeable channels that plays a crucial role in regulating intracellular Ca2+ homeostasis. These channels function as cellular sensors and are stimulated by a variety of physio-chemical stimulus, and endogenous and exogenous ligands. Numerous neuronal diseases are caused by disturbances in the activity of TRP channels, which are abundantly expressed in neuronal cells. When the activity of TRP channels is disturbed under pathological conditions, there is disruption of the homeostasis of neurons via oxidative stress, Ca2+ dyshomeostasis, and mitochondrial dysfunction. Therefore, these channels act as promising therapeutic candidates for pharmacological interventions in several neurological disorders. Thus within this review, we emphasize the function of TRP channels in neurological disorders and highlight the pharmacological modulators that target TRP channels

DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease

Dopamine dyshomeostasis has been acknowledged among the determinants of nigrostriatal neuron degeneration in Parkinson’s disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein αSynuclein (αSyn), whose misfolding and aggregation represent a major trait of PD pathology, triggering αSyn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits αSyn accumulation and hampers αSyn clearance in primary neurons. DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways in neurites. The progressive decline of neuronal homeostasis further leads to dopaminergic neuron loss and motor impairment, as showed in in vivo models. Finally, we developed a specific antibody which detected increased DOPAL-modified αSyn in human striatal tissues from idiopathic PD patients, corroborating the translational relevance of αSyn-DOPAL interplay in PD neurodegeneration.

Plasma Concentrations of Calcium and Risk of Alzheimer Disease-Observational and Genetic Studies.

Dysregulation of calcium ion homeostasis in neurons is well documented in Alzheimer disease (AD), and high plasma calcium concentrations have been associated with cognitive decline in the elderly; however, a potential causal nature for this association has not been elucidated. Plasma calcium ion concentrations of 97 968 individuals from the Copenhagen General Population Study (CGPS) were included and multifactorial Cox regressions using splines or quartiles was performed to investigate the observational association. A plasma calcium ion genome-wide association study (GWAS) was performed in 2 independent subgroups of the CGPS. The plasma calcium ion GWAS and publicly available genomic data sets for plasma total calcium and AD were used to perform the currently most powerful 2-sample Mendelian randomization studies. The hazard ratio for lowest vs highest quartile of the calcium ion concentration was 1.24 (95% CI, 1.08-1.43) for AD. The plasma calcium ion GWAS identified 3 independent loci. None of the genetic instruments for plasma concentrations of calcium ions or total calcium were associated with AD risk. High plasma concentrations of calcium ions were observationally associated with increased risk of AD but genetic associations were not found, suggesting that the observational findings may be due to reverse causation or residual confounding.

Reduced Autophagy in Aged Trigeminal Neurons Causes Amyloid β Diffusion

The relationship between oral health and the development of Alzheimer’s disease (AD) in the elderly is not yet well understood. In this regard, the association between aging or neurodegeneration of the trigeminal nervous system and the accumulation of amyloid-β(1–42) (Aβ42) oligomers in the pathogenesis of AD is unknown. We focused on selective autophagy in the trigeminal mesencephalic nucleus (Vmes) and the diffusion of Aβ42 oligomers with respect to aging of the trigeminal nervous system and whether the degeneration of Vmes neurons affects the diffusion of Aβ42 oligomers. We used female 2- to 8-mo-old transgenic 3xTg-AD mice and App NL-G-F knock-in mice and immunohistochemically examined aging-related changes in selective autophagy and Aβ42 oligomer processing in the Vmes, which exhibits high amyloid-β (Aβ) expression. We induced degeneration of Vmes neurons by extracting the maxillary molars and examined the changes in Aβ42 oligomer kinetics. Autophagosome-like membranes, which stained positive for Aβ, HO-1, and LC3B, were observed in Vmes neurons of 3xTg-AD mice, while there was weak immunoreactivity of the membranes for intraneuronal Aβ in App NL-G-F mice. By contrast, there was strong immunopositivity for extracellular Aβ42 oligomers with the formation of Aβ42 oligomer clusters in App NL-G-F mice. The expression of Rubicon, which indicates age-related deterioration of autophagy, increased the diffusion of Aβ42 oligomer with the age of Vmes neurons. Tooth extraction increased the extracellular immunopositivity for Aβ42 oligomers in App NL-G-F mice. These results suggest that autophagy maintains homeostasis in Vmes neurons and that deterioration of autophagy due to aging or neurodegeneration leads to the diffusion of Aβ42 oligomers into the extracellular space and possibly the development of AD.

Aberrantly activated TAK1 links neuroinflammation and neuronal loss in Alzheimer's disease mouse models.

Neuroinflammation is causally associated with Alzheimer's disease (AD) pathology. Reactive glia cells secrete various neurotoxic factors that impair neuronal homeostasis eventually leading to neuronal loss. Although the glial activation mechanism in AD has been relatively well studied, how it perturbs intraneuronal signaling, which ultimately leads to neuronal cell death, remains poorly understood. Here, we report that compound stimulation with the neurotoxic factors TNF and glutamate aberrantly activates neuronal TAK1 (also known as MAP3K7), which promotes the pathogenesis of AD in mouse models. Glutamate-induced Ca2+ influx shifts TNF signaling to hyper-activate TAK1 enzymatic activity through Ca2+/calmodulin-dependent protein kinase II, which leads to necroptotic cellular damage. Genetic ablation and pharmacological inhibition of TAK1 ameliorated AD-associated neuronal loss and cognitive impairment in the AD model mice. Our findings provide a molecular mechanism linking cytokines, Ca2+ signaling and neuronal necroptosis in AD.