Parabiosis modeling:protocol,application and perspectives

Parabiosis is a surgical method of animal modeling with a long history.It has been widely used in medical research,particularly in the fields of aging,stem cells,neuroscience,and immunity in the past two decades.The protocols for parabiosis have been improved many times and are now widely accepted.However,researchers need to consider many details,from surgical operation to perioperative management,to reduce mortality and maintain the parabiosis union.Although parabiosis has certain inevitable limitations,it still has broad application prospects as an irreplaceable animal model in the medical research field.

Comorbidity Burden of Dementia:A Hospital-Based Retrospective Study from 2003 to 2012 in Seven Cities in China

Dementia is increasing dramatically and imposes a huge burden on society. To date, there is a lack of data on the health status of patients with dementia in China. In an attempt to investigate the comorbidity burden of dementia patients in China at the national level, we enrolled 2,938 patients with Alzheimer＇s disease（AD）, vascular dementia（Va D）, or other types of dementia, who were admitted to tertiary hospitals in seven regions of China from January2003 to December 2012. The Charlson Comorbidity Index（CCI） was used to evaluate the comorbidity burden of the patients with dementia. Among these patients, 53.4% had AD, 26.3% had Va D, and 20.3% had other types of dementia. The CCI was 3.0 ± 1.9 for all patients,3.4 ± 1.8 for those with Va D, and 3.0 ± 2.1 for those with AD. The CCI increased with age in all patients, andthe length of hospital stay and daily expenses rose with age and CCI. Males had a higher CCI and a longer stay than females. Moreover, patients admitted in the last 5 years of the study had a higher CCI than those admitted in the first 5 years. We found that the comorbidity burden of patients with dementia is heavy. These findings provide a better understanding of the overall health status of dementia patients, and help to increase the awareness of clinicians and policy-makers to improve medical care for patients.

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.

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.

Clinical Research on Alzheimer's Disease: Progress and Perspectives

Alzheimer’s disease(AD), the most common type of dementia, is becoming a major challenge for global health and social care. However, the current understanding of AD pathogenesis is limited, and no early diagnosis and disease-modifying therapy are currently available. During the past year, significant progress has been made in clinical research on the diagnosis, prevention, and treatment of AD.In this review, we summarize the latest achievements,including diagnostic biomarkers, polygenic hazard score,amyloid and tau PET imaging, clinical trials targeting amyloid-beta(Ab), tau, and neurotransmitters, early intervention, and primary prevention and systemic intervention approaches, and provide novel perspectives for further efforts to understand and cure the disease.

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.

Association of Polygenic Risk Score with Age at Onset and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease in a Chinese Cohort

To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer’s disease(sAD)and pathological biomarkers in cerebrospinal fluid(CSF),462 sAD patients and 463 age-matched cognitively normal(CN)controls were genotyped for 35 singlenucleotide polymorphisms(SNPs)that are significantly associated with sAD.Then,the alleles found to be associated with sAD were used to build polygenic risk score(PRS)models to represent the genetic risk.Receiver operating characteristic(ROC)analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset.We measured the CSF levels of Aβ42,Aβ42/Aβ40,total tau(T-tau),and phosphorylated tau(P-tau)in a subgroup(60 sAD and 200 CN participants),and analyzed their relationships with the PRSs.We found that 14 SNPs,including SNPs in the APOE,BIN1,CD33,EPHA1,SORL1,and TOMM40 genes,were associated with sAD risk in our cohort.The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls,and were able to predict the incidence rate of sAD and age at onset.Furthermore,the PRSs were correlated with the CSF levels of Aβ42,Aβ42/Aβ40,T-tau,and P-tau.Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD.As genetic risk profiles vary among populations,large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.

Is Alzheimer’s Disease Transmissible in Humans?

Alzheimer’s disease(AD),the most common type of dementia,has been identified as a protein misfolding disease with the accumulation of abnormally folded amyloid-β(Aβ)protein and hyperphosphorylated tau protein in the brain[1,2].Aβ is known to play a crucial role in the pathogenesis of AD.Deposition of Aβ protein in the brain parenchyma causing senile plaques is the obligatory event in AD pathogenesis.Aβ protein is also deposited in the media and adventitia of small and midsized cerebral arteries leading to cerebral amyloid angiopathy(CAA),which is also present in the large majority of AD patents.

Combining Multiple Factors to Predict Alzheimer’s Disease

Alzheimer's disease(AD)is the most common type of dementia that imposes a high burden on caregivers and has substantial economic cost for society.Although there are no drugs available to reverse the progression of AD,a large number of studies have shown that intervention for the risk factors for AD or administration of disease-modifying therapy at the preclinical/prodromal stage yields better outcomes.Therefore,early diagnosis or accurate prediction of AD in healthy populations and preclinical AD is an important prerequisite for effective intervention.