scholarly journals TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus

2021 ◽  
Author(s):  
Anusha Jayaraman ◽  
Thein Htike ◽  
Rachel James ◽  
Carmen Picon ◽  
Richard Reynolds
Keyword(s):  
Pyramidal Neurons ◽  
Neuronal Damage ◽  
Neuronal Loss ◽  
Post Mortem ◽  
Altered Expression ◽  
Neuron Density ◽  
Tnf Superfamily ◽  
Post Mortem Brain ◽  
Show Evidence ◽  
Human Ipsc

The pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimers disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons. The density of phosphoRIPK3+ and phosphoMLKL+ neurons correlated inversely with total neuron density and showed significant sexual dimorphism within the AD cohort. In addition, apoptotic signaling was not significantly activated in the AD brain compared to the control brain. Exposure of human iPSC-derived glutamatergic neurons to TNF increased necroptotic cell death when apoptosis was inhibited, which was significantly reversed by small molecule inhibitors of RIPK1, RIPK3, and MLKL. In the post-mortem AD brain and in human iPSC neurons to TNF, we show evidence of altered expression of proteins of the ESCRT III complex, which has been recently suggested as an antagonist of necroptosis and a possible mechanism by which cells can survive after necroptosis has been triggered. Taken together, our results suggest that neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway.

scholarly journals TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Anusha Jayaraman ◽  
Thein Than Htike ◽  
Rachel James ◽  
Carmen Picon ◽  
Richard Reynolds
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pyramidal Neurons ◽  
Neuronal Damage ◽  
Neuronal Loss ◽  
Post Mortem ◽  
Altered Expression ◽  
Neuron Density ◽  
Show Evidence ◽  
Human Ipsc

AbstractThe pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer’s disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons. The density of phosphoRIPK3 + and phosphoMLKL + neurons correlated inversely with total neuron density and showed significant sexual dimorphism within the AD cohort. In addition, apoptotic signaling was not significantly activated in the AD brain compared to the control brain. Exposure of human iPSC-derived glutamatergic neurons to TNF increased necroptotic cell death when apoptosis was inhibited, which was significantly reversed by small molecule inhibitors of RIPK1, RIPK3, and MLKL. In the post-mortem AD brain and in human iPSC neurons, in response to TNF, we show evidence of altered expression of proteins of the ESCRT III complex, which has been recently suggested as an antagonist of necroptosis and a possible mechanism by which cells can survive after necroptosis has been triggered. Taken together, our results suggest that neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway.

Altered expression of tau exon 10, clk2 and htra2-ß in post mortem brain of patients with Alzheimer’s disease

2004 ◽  
Vol 36 (05) ◽  
Author(s):  
D Glatz ◽  
F Berendt ◽  
F Faltraco ◽  
AM Hartmann ◽  
H Hampel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Post Mortem ◽  
Altered Expression ◽  
Post Mortem Brain ◽  
Exon 10

scholarly journals Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Boris Guennewig ◽  
Julia Lim ◽  
Lee Marshall ◽  
Andrew N. McCorkindale ◽  
Patrick J. Paasila ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Sequencing ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Post Mortem ◽  
Tau Pathology ◽  
Membrane Spanning ◽  
Immune Related Genes ◽  
Vesicle Secretion

AbstractTau pathology in Alzheimer’s disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The ‘early’ AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

P1-155: Post-Mortem Brain Tissue Characterisation of Inflammatory and Pathological Hallmarks of Alzheimer’s Disease During Disease Progression

2016 ◽  
Vol 12 ◽  
pp. P462-P462
Author(s):  
Martina M. Hughes ◽  
Beatriz G. Perez-Nievas ◽  
Claire Troakes ◽  
Michael Perkinton ◽  
Diane P. Hanger ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Brain Tissue ◽  
Post Mortem ◽  
Tissue Characterisation ◽  
Post Mortem Brain

scholarly journals The choice of embedding media affects image quality, tissue R 2 * , and susceptibility behaviors in post‐mortem brain MR microscopy at 7.0T

2018 ◽  
Vol 81 (4) ◽  
pp. 2688-2701 ◽  
Author(s):  
Petr Dusek ◽  
Vince Istvan Madai ◽  
Till Huelnhagen ◽  
Erik Bahn ◽  
Radoslav Matej ◽  
...  
Keyword(s):  
Image Quality ◽  
Post Mortem ◽  
Mr Microscopy ◽  
Post Mortem Brain

scholarly journals Natriuretic Peptides in Post-mortem Brain Tissue and Cerebrospinal Fluid of Non-demented Humans and Alzheimer’s Disease Patients

2018 ◽  
Vol 12 ◽  
Author(s):  
Simin Mahinrad ◽  
Marjolein Bulk ◽  
Isabelle van der Velpen ◽  
Ahmed Mahfouz ◽  
Willeke van Roon-Mom ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Brain Tissue ◽  
Natriuretic Peptides ◽  
Post Mortem ◽  
Post Mortem Brain

scholarly journals Altered White Matter and Layer VIb Neurons in Heterozygous Disc1 Mutant, a Mouse Model of Schizophrenia

2020 ◽  
Vol 14 ◽  
Author(s):  
Shin-Hwa Tsai ◽  
Chih-Yu Tsao ◽  
Li-Jen Lee
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
Pyramidal Neurons ◽  
Sensory Information ◽  
Morphological Characters ◽  
Cortical Layer ◽  
Type I ◽  
Brain Functions ◽  
Neuron Density ◽  
Subplate Neurons

Increased white matter neuron density has been associated with neuropsychiatric disorders including schizophrenia. However, the pathogenic features of these neurons are still largely unknown. Subplate neurons, the earliest generated neurons in the developing cortex have also been associated with schizophrenia and autism. The link between these neurons and mental disorders is also not well established. Since cortical layer VIb neurons are believed to be the remnant of subplate neurons in the adult rodent brain, in this study, we aimed to examine the cytoarchitecture of neurons in cortical layer VIb and the underlying white matter in heterozygous Disc1 mutant (Het) mice, a mouse model of schizophrenia. In the white matter, the number of NeuN-positive neurons was quite low in the external capsule; however, the density of these cells was found increased (54%) in Het mice compared with wildtype (WT) littermates. The density of PV-positive neurons was unchanged in the mutants. In the cortical layer VIb, the density of CTGF-positive neurons increased (21.5%) in Het mice, whereas the number of Cplx3-positive cells reduced (16.1%) in these mutants, compared with WT mice. Layer VIb neurons can be classified by their morphological characters. The morphology of Type I pyramidal neurons was comparable between genotypes while the dendritic length and complexity of Type II multipolar neurons were significantly reduced in Het mice. White matter neurons and layer VIb neurons receive synaptic inputs and modulate the process of sensory information and sleep/arousal pattern. Aberrances of these neurons in Disc1 mutants implies altered brain functions in these mice.

scholarly journals Emergence of distinct and heterogeneous strains of amyloid beta as Alzheimer′s disease progresses in Down syndrome

2021 ◽  
Author(s):  
Alison M Maxwell ◽  
Peng Yuan ◽  
Brianna M Rivera ◽  
Wilder Schaaf ◽  
Mihovil Mladinov ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Amyloid Beta ◽  
Fluorescent Probes ◽  
Clinical Symptoms ◽  
Critical Role ◽  
Phenotypic Heterogeneity ◽  
Post Mortem ◽  
Strain Profile ◽  
Post Mortem Brain ◽  
And Control

Amyloid beta (A&#946) is thought to play a critical role in the pathogenesis of Alzheimer&#8242s disease (AD). Prion-like Aβ polymorphs, or strains, can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of A&#946 that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Down syndrome (DS), as the most common genetic cause of AD, presents promising opportunities to compare such features between early and advanced AD. In this work, we evaluate the neuropathology and A&#946 strain profile in the post-mortem brain tissues of 210 DS, AD, and control individuals. We assayed the levels of various A&#946 and tau species and used conformation-sensitive fluorescent probes to detect differences in A&#946 strains among individuals and populations. We found that these cohorts have some common but also some distinct strains from one another, with the most heterogeneous populations of A&#946 emerging in subjects with high levels of AD pathology. The emergence of distinct strains in DS at these later stages of disease suggests that the confluence of aging, pathology, and other DS-linked factors may favor conditions that generate strains that are unique from sAD.

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