Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease

The extracellular domain(p75ECD)of p75 neurotrophin receptor(p75NTR)antagonizes Aβ neurotoxicity and promotes Aβclearance in Alzheimer’s disease(AD).The impaired shedding of p75ECD is a key pathological process in AD,but its regulatory mechanism is largely unknown.This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD(p75ECD-NAbs)in AD patients and their effects on AD pathology.We found that the cerebrospinal fluid(CSF)level of p75ECD-NAbs was increased in AD,and negatively associated with the CSF levels of p75ECD.Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain,as well as worse cognitive functions than the control groups,which were immunized with Re-p75ECD(the reverse sequence of p75ECD)and phosphate-buffered saline,respectively.These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance,providing a novel insight into the role of autoimmunity and p75NTR in AD.

Composing Like an Ancient Chinese Poet:Learn to Generate Rhythmic Chinese Poetry

Automatic generation of Chinese classical poetry is still a challenging problem in artificial intelligence.Re-cently,Encoder-Decoder models have provided a few viable methods for poetry generation.However,by reviewing the pri-or methods,two major issues still need to be settled:1)most of them are one-stage generation methods without further polishing;2)they rarely take into consideration the restrictions of poetry,such as tone and rhyme.Intuitively,some an-cient Chinese poets tended first to write a coarse poem underlying aesthetics and then deliberated its semantics;while oth-ers first create a semantic poem and then refine its aesthetics.On this basis,in order to better imitate the human creation procedure of poems,we propose a two-stage method(i.e.,restricted polishing generation method)of which each stage fo-cuses on the different aspects of poems(i.e.,semantics and aesthetics),which can produce a higher quality of generated poems.In this way,the two-stage method develops into two symmetrical generation methods,the aesthetics-to-semantics method and the semantics-to-aesthetics method.In particular,we design a sampling method and a gate to formulate the tone and rhyme restrictions,which can further improve the rhythm of the generated poems.Experimental results demon-strate the superiority of our proposed two-stage method in both automatic evaluation metrics and human evaluation met-rics compared with baselines,especially in yielding consistent improvements in tone and rhyme.

Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-βand Prevents Alzheimer’s Disease-Type Pathology and Cognitive Deficits

Deficiencies in the clearance of peripheral amyloidβ(Aβ)play a crucial role in the progression of Alzheimer’s disease(AD).Previous studies have shown that the ability of blood monocytes to phagocytose Aβis decreased in AD.However,the exact mechanism of Aβclearance dysfunction in AD monocytes remains unclear.In the present study,we found that blood monocytes in AD mice exhibited decreases in energy metabolism,which was accompanied by cellular senescence,a senescence-associated secretory phenotype,and dysfunctional phagocytosis of Aβ.Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβin vivo and in vitro.Moreover,enhancing blood monocyte Aβphagocytosis by improving energy metabolism alleviated brain Aβdeposition and neuroinflammation and eventually improved cognitive function in AD mice.This study reveals a new mechanism of impaired Aβphagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.

Polysaccharide Krestin Prevents Alzheimer’s Disease-type Pathology and Cognitive Deficits by Enhancing Monocyte Amyloid-βProcessing

Deficits in the clearance of amyloidβprotein(Aβ)by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer’s disease(AD).Impaired uptake of Aβby dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβclearance in AD.In the current study,flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin(PSK)on AD-related pathology in vitro and in vivo.We found that PSK,widely used in therapy for various cancers,has the potential to enhance Aβuptake and intracellular processing by human monocytes in vitro.After administration of PSK by intraperitoneal injection,APP/PS1 mice performed better in behavioral tests,along with reduced Aβdeposition,neuroinflammation,neuronal loss,and tau hyperphosphorylation.These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβclearance by blood monocytes and alleviating AD-like pathology.

Spicy food consumption is associated with cognition and cerebrospinal fluid biomarkers of Alzheimer disease

Background:Recent studies suggest that a healthy diet helps to prevent the development of Alzheimer disease(AD).This study aimed to investigate whether spicy food consumption is associated with cognition and cerebrospinal fluid(CSF)biomarkers of AD in the Chinese population.Methods:We enrolled 55 AD patients and 55 age-and gender-matched cognitively normal(CN)subjects in a case-control study,as well as a cohort of 131 participants without subjective cognitive decline(non-AD)in a cross-sectional study.Spicy food consumption was assessed using the Food Frequency Questionnaire(FFQ).Associations of FFQ scores with cognition and CSF biomarkers of AD were analyzed.Results:In the case-control study,spicy food consumption was lower in AD patients than that in CNs(4.0[4.0-8.0]vs.8.0[4.5-10.0],P<0.001);FFQ scores were positively associated with Mini-Mental Status Examination scores in the total sample(r=0.218,P=0.014).In the cross-sectional study,the association between spicy food consumption and cognition levels was verified in non-AD subjects(r=0.264,P=0.0023).Moreover,higher FFQ scores were significantly associated with higherβ-Amyloid(1-42)(Aβ42)levels and lower phospho-tau/Aβ42 and total tau/Aβ42 ratios in the CSF of non-AD subjects(P<0.05).Conclusion:Spicy food consumption is closely related to higher cognition levels and reversed AD biomarkers in the CSF,suggesting that a capsaicin-rich diet might have the potential to modify the cognitive status and cerebral pathologies associated with AD.

Naturally-Occurring Antibodies Against Bim are Decreased in Alzheimer’s Disease and Attenuate AD-type Pathology in a Mouse Model

Increased neuronal apoptosis is an important pathological feature of Alzheimer’s disease(AD).The Bcl-2-interacting mediator of cell death(Bim)mediates amyloid-beta(Aβ)-induced neuronal apoptosis.Naturally-occurring antibodies against Bim(NAbs-Bim)exist in human blood,with their levels and functions unknown in AD.In this study,we found that circulating NAbs-Bim were decreased in AD patients.Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions.Furthermore,NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aβdeposition,tau hyperphosphorylation,microgliosis,and neuronal apoptosis in APP/PS1 mice.In vitro investigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein.These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.