Endoplasmic Reticulum Stress Induces the Early Appearance of Pro-apoptotic and Anti-apoptotic Proteins in Neurons of Five Familial Alzheimer＇s Disease Mice

Background： Amyloid β （Aβ） deposits and the endoplasmic reticulum stress （ERS） are both well established in the development and progression of Alzheimer＇s disease （AD）. However, the mechanism and role of Aβ-induced ERS in AD-associated pathological progression remain to be elucidated. Methods： The five familial AD （5×FAD） mice and wild-type （WT） mice aged 2, 7, and 12 months were used in the present study. Monis water maze test was used to evaluate their cognitive performance, lmmunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic （CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12） and anti-apoptotic factors （chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN 1]） in the ERS-associated unfolded protein response （UPR） pathway. Results： Compared with age-matched WT mice, 5 xFAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months （all P 〈 0.05）. Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN 1, were significantly increased when compared with those in age-matched WT mice （all P 〈 0.05）. Moreover, ERS occurred mainly in neurons, not in astrocytes. Conclusions： These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aβ aggregation in neurons.

获得性神经性肌强直自发放电的起源:一项巨大EMG研究

Objective: To study the generator sites of spontaneous discharges in patients with immune-mediated neuromyotonia. Methods: Macro EMGs triggered by both spontaneously and voluntarily activated single action potentials were recorded and the mean peak-to-peak amplitude and area of the macro motor unit potentials were compared in two patients with typical acquired neuromyotonia having positive antibodies against voltage-gated potassium channels. Results: Mean peak-to-peak amplitude and area of Macro EMG motor unit potentials (macro MUPs) triggered by spontaneous discharges were significantly smaller than those triggered by voluntary activation in both patients. However, a few macro MUPs triggered by spontaneous discharges resembled those triggered by voluntary activation. Conclusions: Spontaneous discharges in two patients with immune-mediated neuromyotonia seem to be mostly generated at sites distal to the terminal axon branching points. Significance: This finding may provide a new insight in the understanding of spontaneous discharges in immune-mediated neuromyotonia.

Reduction of Glucose Metabolism in Olfactory Bulb is an Earlier Alzheimer＇s Disease-related Biomarker in 5XFAD Mice

Background：Early diagnosis assumes a vital role in an effective treatment of Alzheimer＇s disease （AD）.Most of the current studies can only make anAD diagnosis after the manifestation of typical clinical symptoms.The present study aimed to investigate typical and other biomarkers of AD to find a possible early biomarker.Methods：A total of 14 5XFAD mice （at 3 and 6 months old）,with 14 age-matched wild-type （WT） mice as control,were enrolled in this case-control study.Morris water maze test was performed to evaluate the cognitive function;buried food pellet test and olfactory maze test were employed to investigate the olfactory function;immunofluorescence to detect amyloid deposition and positron emission tomography to examine 2-deoxy-2-（18F） fluoro-D-glucose （[18F]-FDG） uptake in the hippocampus and cerebral cortex.Results：With the increasing age,cognitive performance （P =0.0262） and olfactory function were significantly deteriorated （day 1 P =0.0012,day 2 P =0.0031,day 3 P =0.0160,respectively） and the （18F）-FDG uptake was markedly decreased in multi-cerebral regions including the olfactory bulb （P 〈 0.0001）,hippocampus （P =0.0121）,and cerebral cortex （P 〈 0.0001）.Of note,in 3-month-old 5XFAD mice,a significant decline of （18F）-FDG uptake in the olfactory bulb was found when compared with that of age-matched WT mice （P =0.023） while no significant difference was present when the uptakes in other cerebral regions were compared.Conclusions：The decline of （18F）-FDG uptake in the olfactory bulb occurs earlier than other incidents,serving as an earlier in vivo biological marker of AD in 5XFAD mice and making early diagnosis of AD possibly.

Ginsenoside Rg1 and astaxanthin act on the hypothalamus to protect female mice against reproductive aging

To the Editor:Female infertility due to reproductive aging has become a prominent concern in the population.Evidence indicates that oxidative stress is one of the dominant mechanisms underlying reproductive aging.[1,2]Although female reproductive aging involves gradual changes to the hypothalamic-pituitary-ovarian(HPO)axis,previous studies support a key involvement of the hypothalamus.[3,4]In our recent dataset,it was shown that estrogen-induced oxidative stress led to the senescence of hypothalamic astrocytes that predated reproductive dysfunction.[3]Growing evidence has demonstrated that antioxidants might delay reproductive aging by reducing oxidative damage to ovaries.[1,2]However,the effect of antioxidants on the hypothalamus has not been reported.Astaxanthin(AST),3,3'-dihydroxy-β-carotene-4,4'-dione,is a xanthophyll carotenoid found predominantly in marine animals such as salmon,trout,lobster,and shrimp.Ginseng is a tonic drug in traditional Chinese medicine.Ginsenoside Rg1,a class of steroidal glycosides,is a prominent active anti-aging ingredient within ginseng responsible for these effects.Notably,the two antioxidants freely cross the blood-brain barrier.In this study,we evaluated the effects of these two natural compounds on the hypothalamus and ovaries in protecting female mice from reproductive aging.

Preserving cognitive function in patients with Alzheimer's disease:The Alzheimer's disease neuroprotection research initiative(ADNRI)

The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.