Striatal oxidative damages and neuroinflammation correlate with progression and survival of Lewy body and Alzheimer diseases

Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas.The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated.In this observational study,we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases(LBDs)and Alzheimer disease(AD),shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration.We performed Spearman and Mantel-Cox analyses to investigate how oxidative stress and neuroinflammation exert comprehensive effects on disease progression and survival.Disease progression in LBDs correlated positively with poly(ADP-Ribose)and triggering receptors expressed on myeloid cell 2 levels in the striatum of LBD cohorts,indicating that potential parthanatos was a dominant feature of worsening disease progression and might contribute to switching microglial inflammatory phenotypes.Disease progression in AD corresponds negatively with 8-oxo-7,8-dihydro-2′-deoxyguanosine(8-oxo-d G)and myeloperoxidase concentrations in the striatum,suggesting that possible mitochondria dysfunction may be involved in the progression of AD via a mechanism ofβ-amyloid entering the mitochondria and subsequent free radicals generation.Patients with lower striatal 8-oxo-d G and myeloperoxidase levels had a survival advantage in AD.The age of onset also affected disease progression.Tissue requests for the postmortem biochemistry,genetics,and autoradiography studies were approved by the Washington University Alzheimer's Disease Research Center(ADRC)Biospecimens Committee(ethics approval reference number:T1705,approval date:August 6,2019).Recombinant DNA and Hazardous Research Materials were approved by the Washington University Environmental Health&Safety Biological Safety Committee(approval code:3739,approval date:February 25,2020).Radioactive Material Authorization was approved by the Washington University Environmental Health&Safety Radiation Safety Committee(approval code:1056,approval date:September 18,2019).

Clinical Experience of Professor Du Xiaoquan's Treatment of Spleen and Spleen Disease

Professor du Xiaoquan is a famous Chinese medicine in Shaanxi Province,a master's tutor,a professor of Shaanxi University of traditional Chinese Medicine,a director of the Department of traditional Chinese Medicine,and a professor of Shen Shuwen,a national famous old Chinese medicine.

Politics and Salus Populi:Hobbes and the Sovereign as Physician of the State

In his masterpiece Leviathan(1651),Thomas Hobbes used a series of rhetorical devices in order to persuade the English reader of the truth of his political theories and of his civil science.The first rhetorical device is the engraved frontispiece of the book,where the sword of justice held by the sovereign is also a powerful sword of rhetoric(as shown by the table depicting Rhetoric in a Martianus Capella’s manuscript owned by the Duke of Urbino).Moreover,Hobbes employs directly the metaphor of the state as a body politic and the analogy of the sovereign as the soul of the state and he also refers—though indirectly—to the Platonic analogy of the sovereign as physician of the state,evoking political thinkers,such as King James VI&I and Edward Forset.

The role of quercetin on the survival of neuron-like PC12 cells and the expression of α-synuclein

Both genetic and environmental factors are important in the pathogenesis of Parkinson＇s disease. As α-synuclein is a major constituent of Lewy bodies, a pathologic hallmark of Parkinson＇s disease, genetic aspects of α-synuclein is widely studied. However, the influence of dietary factors such as quercetin on α-synuclein was rarely studied. Herein we aimed to study the neuroprotective role of quercetin against various toxins affecting apoptosis, autophagy and aggresome, and the role of quercetin on α-synuclein expression. PC12 cells were pre-treated with quercetin（100, 500, 1,000 μM） and then together with various drugs such as 1-methyl-4-phenylpyridinium（MPP＋; a free radical generator）, 6-hydroxydopamine（6-OHDA; a free radical generator）, ammonium chloride（an autophagy inhibitor）, and nocodazole（an aggresome inhibitor）. Cell viability was determined using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltertazolium bromide（MTT） assay. Apoptosis was detected by annexin V-fluorescein isothiocyanate and propidium iodide through the use of fluorescence activated cell sorter. α-Synuclein expression was detected by western blot assay and immunohistochemistry. The role of α-synuclein was further studied by knocking out α-synuclein using RNA interference. Cell viability increased at lower concentrations（100 and 500 μM） of quercetin but decreased at higher concentration（1,000 μM）. Quercetin exerted neuroprotective effect against MPP＋, ammonium chloride and nocodazole at 100 μM. MPP＋ induced apoptosis was decreased by 100 μM quercetin. Quercetin treatment increased α-synuclein expression. However, knocking out α-synuclein exerted no significant effect on cell survival. In conclusion, quercetin is neuroprotective against toxic agents via affecting various mechanisms such as apoptosis, autophagy and aggresome. Because α-synuclein expression is increased by quercetin, the role of quercetin as an environmental factor in Parkinson＇s disease pathogenesis needs further investigation.

Loss of tau expression attenuates neurodegeneration associated with α-synucleinopathy

Background: Neuronal dysfunction and degeneration linked to α-synuclein (αS) pathology is thought to be responsible for the progressive nature of Parkinson’s disease and related dementia with Lewy bodies. Studies have indicated bidirectional pathological relationships between αS pathology and tau abnormalities. We recently showed that A53T mutant human αS (HuαS) can cause post-synaptic and cognitive deficits that require microtubule-associated protein tau expression. However, the role of tau in the development of αS pathology and subsequent neuronal dysfunction has been controversial. Herein, we set out to determine the role of tau in the onset and progression of αS pathology (α-synucleinopathy) using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression. Methods: Transgenic mice expressing A53T mutant HuαS (TgA53T) were crossed with mTau−/− mice to generate TgA53T/mTau−/−. To achieve more uniform induction of α-synucleinopathy in mice, we used intramuscular injections of αS preformed fibrils (PFF) in non-transgenic (nTg), TgA53T, TgA53T/mTau−/−, and mTau−/− mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage. Results: Loss of tau expression significantly delayed the onset of motor deficits in the TgA53T model and the progression of α-synucleinopathy disease, as evidenced by a significant reduction in histopathological and behavioral markers of neurodegeneration and disease, and a significant improvement in survival. In vitro application of PFF to primary mouse hippocampal neurons demonstrated no changes in PFF uptake and processing or pS129 αS aggregation as a function of tau expression. However, PFF-induced neurotoxicity, including morphological deficits in nTg neurons, was prevented with tau removal. Conclusions: Collectively, our data suggest that tau is likely acting downstream of αS pathology to affect neuronal homeostasis and survival. This work further supports the investigation of tau in α-synucleinopathies to identify novel disease-modifying therapeutic strategies.