Effects of silica nanoparticles on endolysosome function in primary cultured neurons

Silica nanoparticles (SiNPs) have been used as vehicles for drug delivery, molecular detection, and cellular manipulations in nanoneuromedicine. SiNPs may cause adverse effects in the brain including neurotoxicity, neuroinflammation, neurodegeneration, and enhancing levels of amyloid beta (Aβ) protein—all pathological hallmarks of Alzheimer’s disease. Therefore, the extent to which SiNPs influence Aβ generation and the underlying mechanisms by which this occurs deserve investigation. Our studies were focused on the effects of SiNPs on endolysosomes which uptake, traffic, and mediate the actions of SiNPs. These organelles are also where amyloidogenesis largely originates. We found that SiNPs, in primary cultured hippocampal neurons, accumulated in endolysosomes and caused a rapid and persistent deacidification of endolysosomes. SiNPs significantly reduced endolysosome calcium stores as indicated by a significant reduction in the ability of the lysosomotropic agent glycyl-l-phenylalanine 2-naphthylamide (GPN) to release calcium from endolysosomes. SiNPs increased Aβ1–40 secretion, whereas 2 agents that acidified endolysosomes, ML-SA1 and CGS21680, blocked SiNP-induced deacidification and increased generation of Aβ1–40. Our findings suggest that SiNP-induced deacidification of and calcium release from endolysosomes might be mechanistically linked to increased amyloidogenesis. The use of SiNPs might not be the best nanomaterial for therapeutic strategies against Alzheimer’s disease and other neurological disorders linked to endolysosome dysfunction.

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A Large-scale Comparison of Cortical and Subcortical Structural Segmentation Methods in Alzheimer’s Disease: a Statistical Approach

10.1101/2020.08.18.256321 ◽

2020 ◽

Author(s):

Jafar Zamani ◽

Ali Sadr ◽

Amir-Homayoun Javadi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Automated Segmentation ◽

Resonance Imaging ◽

Brain Areas ◽

Segmentation Methods ◽

Magnetic Resonance Imaging Mri ◽

Underlying Mechanisms ◽

The Brain

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that leads to anatomical atrophy, as evidenced by magnetic resonance imaging (MRI). Automated segmentation methods are developed to help with the segmentation of different brain areas. However, their reliability has yet to be fully investigated. To have a more comprehensive understanding of the distribution of changes in AD, as well as investigating the reliability of different segmentation methods, in this study we compared volumes of cortical and subcortical brain segments, using automated segmentation methods in more than 60 areas between AD and healthy controls (HC).MethodsA total of 44 MRI images (22 AD and 22 HC, 50% females) were taken from the minimal interval resonance imaging in Alzheimer’s disease (MIRIAD) dataset. HIPS, volBrain, CAT and BrainSuite segmentation methods were used for the subfields of hippocampus, and the rest of the brain.ResultsWhile HIPS, volBrain and CAT showed strong conformity with the past literature, BrainSuite misclassified several brain areas. Additionally, the volume of the brain areas that successfully discriminated between AD and HC showed a correlation with mini mental state examination (MMSE) scores. The two methods of volBrain and CAT showed a very strong correlation. These two methods, however, did not correlate with BrainSuite.ConclusionOur results showed that automated segmentation methods HIPS, volBrain and CAT can be used in the classification of AD and HC. This is an indication that such methods can be used to inform researchers and clinicians of underlying mechanisms and progression of AD.

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Cannabinoid CB1 Receptor-Dependent Long-Term Depression in Autaptic Excitatory Neurons

Journal of Neurophysiology ◽

10.1152/jn.00266.2009 ◽

2009 ◽

Vol 102 (2) ◽

pp. 1160-1171 ◽

Cited By ~ 23

Author(s):

Ryan Kellogg ◽

Ken Mackie ◽

Alex Straiker

Keyword(s):

Hippocampal Neurons ◽

Single Neuron ◽

Calcium Stores ◽

Short Term ◽

Long Term Depression ◽

Erk Activation ◽

Arachidonoyl Glycerol ◽

The Brain ◽

Cultured Hippocampal Neurons

Long-term depression (LTD) of synaptic signaling—lasting from tens of minutes to hours or longer—is a widespread form of synaptic plasticity in the brain. Neurons express diverse forms of LTD, including autaptic LTD (autLTD) observed in cultured hippocampal neurons, the mechanism of which remains unknown. We have recently reported that autaptic neurons express both endocannabinoid-mediated depolarization-induced suppression of excitation (DSE) and metabotropic suppression of excitation (MSE). We now report that activating cannabinoid CB1 receptors is necessary for the induction of autLTD. Most surprisingly, CB1 does not induce autLTD via the Gi/o proteins typically activated by this receptor nor with Gs. Rather, the requirements of presynaptic phospholipase C and filled calcium stores suggest Gq. In autLTD, a 3- to 4-min activation of the receptor by the endocannabinoid 2-arachidonoyl glycerol leads to prolonged inhibition while leaving short-term inhibition (e.g., DSE) intact. autLTD requires activation of both metabo- and ionotropic glutamate receptors. autLTD also requires MEK/ERK activation. Under certain conditions, one or more DSE stimuli will elicit autLTD. It is becoming evident that cannabinoids mediate multiple forms of plasticity at a single synapse, stretching temporally from tens of seconds (DSE/MSE) to tens of minutes (autLTD) to hours (CB1 desensitization). Our findings imply a remarkable flexibility for the cannabinoid signaling system whereby discrete mechanisms of CB1 activation within a single neuron yield temporally and mechanistically distinct forms of plasticity.

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Impairments of neural circuit function in Alzheimer's disease

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0429 ◽

2016 ◽

Vol 371 (1700) ◽

pp. 20150429 ◽

Cited By ~ 84

Author(s):

Marc Aurel Busche ◽

Arthur Konnerth

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hippocampal Neurons ◽

Large Scale ◽

Neural Circuit ◽

Essential Feature ◽

Amyloid Β ◽

Amyloid Plaque ◽

Aβ Oligomers ◽

The Brain

An essential feature of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) peptides in the brain, many years to decades before the onset of overt cognitive symptoms. We suggest that during this very extended early phase of the disease, soluble Aβ oligomers and amyloid plaques alter the function of local neuronal circuits and large-scale networks by disrupting the balance of synaptic excitation and inhibition ( E / I balance) in the brain. The analysis of mouse models of AD revealed that an Aβ-induced change of the E / I balance caused hyperactivity in cortical and hippocampal neurons, a breakdown of slow-wave oscillations, as well as network hypersynchrony. Remarkably, hyperactivity of hippocampal neurons precedes amyloid plaque formation, suggesting that hyperactivity is one of the earliest dysfunctions in the pathophysiological cascade initiated by abnormal Aβ accumulation. Therapeutics that correct the E / I balance in early AD may prevent neuronal dysfunction, widespread cell loss and cognitive impairments associated with later stages of the disease. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

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L-3-n-Butylphthalide improves synaptic and dendritic spine plasticity and ameliorates neurite pathology in Alzheimer’s disease mouse model and cultured hippocampal neurons

Molecular Neurobiology ◽

10.1007/s12035-020-02183-y ◽

2020 ◽

Author(s):

Longjian Huang ◽

Jiaqi Lan ◽

Jingshu Tang ◽

Yuying Kang ◽

Xinhong Feng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Dendritic Spine ◽

Hippocampal Neurons ◽

Spine Plasticity ◽

Cultured Hippocampal Neurons

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Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer’s Disease

Nutrients ◽

10.3390/nu10111765 ◽

2018 ◽

Vol 10 (11) ◽

pp. 1765 ◽

Cited By ~ 57

Author(s):

Vo Giau ◽

Si Wu ◽

Angelo Jamerlan ◽

Seong An ◽

SangYun Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Bidirectional Communication ◽

The Central Nervous System ◽

Brain And Behavior ◽

Underlying Mechanisms ◽

And Behavior ◽

The Impact ◽

The Brain

The bidirectional communication between the central nervous system (CNS) and the gut microbiota plays a pivotal role in human health. Increasing numbers of studies suggest that the gut microbiota can influence the brain and behavior of patients. Various metabolites secreted by the gut microbiota can affect the cognitive ability of patients diagnosed with neurodegenerative diseases. Nearly one in every ten Korean senior citizens suffers from Alzheimer’s disease (AD), the most common form of dementia. This review highlights the impact of metabolites from the gut microbiota on communication pathways between the brain and gut, as well as the neuroinflammatory roles they may have in AD patients. The objectives of this review are as follows: (1) to examine the role of the intestinal microbiota in homeostatic communication between the gut microbiota and the brain, termed the microbiota–gut–brain (MGB) axis; (2) to determine the underlying mechanisms of signal dysfunction; and (3) to assess the impact of signal dysfunction induced by the microbiota on AD. This review will aid in understanding the microbiota of elderly people and the neuroinflammatory roles they may have in AD.

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Root-Securing and Brain-Fortifying Liquid Upregulates Caveolin-1 in Cell Model with Alzheimer’s Disease through Inhibiting Tau Phosphorylation

Neurology Research International ◽

10.1155/2017/6248351 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Depei Yuan ◽

Chuhua Zeng ◽

Qianfeng Chen ◽

Fengjie Wang ◽

Lin Yuan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Hippocampal Neurons ◽

Cell Model ◽

Tau Phosphorylation ◽

Caveolin 1 ◽

Sd Rats ◽

A Cell ◽

Underlying Mechanisms

In order to explore the effect of root-securing and brain-fortifying Liquid- (RSBFL-) mediated caveolin-1 (CAV-1) on phosphorylation of Tau protein and to uncover underlying mechanisms of RSBFL for the prevention and treatment of Alzheimer’s disease (AD), hippocampal neurons isolated from neonatal SD rats and cultured in DMEM-F12 medium were induced by exogenous Aβ1–42 to establish a cell model with AD. Meanwhile, pEGFP-C1-CAV1 and CAV1-shRNA plasmids were transfected into hippocampal neurons for CAV-1 overexpression and silence, respectively. The serum containing RSBFL was prepared for the intervention of AD model cells. The expression of CAV-1, GSK-3β, and p-Tau in normal hippocampal neurons and AD model cells in the presence of serum containing RSBFL was evaluated. The model hippocampal neurons with AD induced by Aβ1–42 revealed an obvious CAV-1 inhibition, enhanced GSK-3βactivity, and abnormal Tau phosphorylation. In contrast, the treatment with serum containing RSBFL could upregulate CAV-1 in AD hippocampal neurons (P<0.05) with improved p-GSK-3βSer9and reduced p-GSK-3βTyr216(P<0.01), as well as suppressed abnormal phosphorylation of Tau protein. Therefore, RSBFL has an excellent protective effect on hippocampal neurons through increasing CAV-1 expression, inhibiting GSK-3βactivity, and reducing excessive abnormal phosphorylation of Tau protein.

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Biomarkers for Microglial Activation in Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/939426 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 9

Author(s):

Ronald Lautner ◽

Niklas Mattsson ◽

Michael Schöll ◽

Kristin Augutis ◽

Kaj Blennow ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Microglial Activation ◽

Inflammatory Responses ◽

Innate Immune ◽

First Line ◽

The Central Nervous System ◽

Underlying Mechanisms ◽

The Brain ◽

Neuroimaging Techniques

Intensive research over the last decades has provided increasing evidence for neuroinflammation as an integral part in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Inflammatory responses in the central nervous system (CNS) are initiated by activated microglia, representing the first line of the innate immune defence of the brain. Therefore, biochemical markers of microglial activation may help us understand the underlying mechanisms of neuroinflammation in AD as well as the double-sided qualities of microglia, namely, neuroprotection and neurotoxicity. In this paper we summarize candidate biomarkers of microglial activation in AD along with a survey of recent neuroimaging techniques.

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Transferrin Biosynthesized in the Brain Is a Novel Biomarker for Alzheimer’s Disease

Metabolites ◽

10.3390/metabo11090616 ◽

2021 ◽

Vol 11 (9) ◽

pp. 616

Author(s):

Kyoka Hoshi ◽

Hiromi Ito ◽

Eriko Abe ◽

Takashi J. Fuwa ◽

Mayumi Kanno ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hippocampal Neurons ◽

Neurological Diseases ◽

Ultra Performance Liquid Chromatography ◽

Cell Type ◽

Post Translational Modification ◽

A Cell ◽

Cell Type Specific ◽

The Brain

Glycosylation is a cell type-specific post-translational modification that can be used for biomarker identification in various diseases. Aim of this study is to explore glycan-biomarkers on transferrin (Tf) for Alzheimer’s disease (AD) in cerebrospinal fluid (CSF). Glycan structures of CSF Tf were analyzed by ultra-performance liquid chromatography followed by mass spectrometry. We found that a unique mannosylated-glycan is carried by a Tf isoform in CSF (Man-Tf). The cerebral cortex contained Man-Tf as a major isofom, suggesting that CSF Man-Tf is, at least partly, derived from the cortex. Man-Tf levels were analyzed in CSF of patients with neurological diseases. Concentrations of Man-Tf were significantly increased in AD and mild cognitive impairment (MCI) comparing with other neurological diseases, and the levels correlated well with those of phosphorylated-tau (p-tau), a representative AD marker. Consistent with the observation, p-tau and Tf were co-expressed in hippocampal neurons of AD, leading to the notion that a combined p-tau and Man-Tf measure could be a biomarker for AD. Indeed, levels of p-tau x Man-Tf showed high diagnostic accuracy for MCI and AD; 84% sensitivities and 90% specificities for MCI and 94% sensitivities and 89% specificities for AD. Thus Man-Tf could be a new biomarker for AD.

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Longitudinal Changes in Individual BrainAGE in Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

GeroPsych ◽

10.1024/1662-9647/a000074 ◽

2012 ◽

Vol 25 (4) ◽

pp. 235-245 ◽

Cited By ~ 64

Author(s):

Katja Franke ◽

Christian Gaser

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Healthy Aging ◽

Brain Aging ◽

Elderly Subjects ◽

Additional Increase ◽

Longitudinal Changes ◽

Novel Method ◽

The Brain

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

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