Chun-Rong Liang

A study on the association between infectious burden and Alzheimer's disease

Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between infectious burden (IB) and Alzheimers disease (AD) was examined.

Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits

Significance Alzheimer’s disease (AD) is a devastating disease that results in the progressive cognitive deficits of elderly and has become one of major social and economic burdens worldwide. There is no effective drug or therapy to prevent or halt the progressive cognitive dysfunctions due to the complex mechanisms such as accumulation of amyloid-β (Aβ), increase in oxidative stress, and formation of neurofibrillary tangle that drive the development of the disease. We found here that Edaravone, a drug that has been used for ischemic stroke, is able to prevent and treat AD by targeting multiple pathways of AD pathogenesis and rescuing the cognitive deficits of a mouse model of AD. Our study suggests Edaravone is a promising drug candidate for AD. Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.

p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer's disease.

In Alzheimer’s disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer’s patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.

An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect.

BackgroundSenile plaques consisting of amyloid-beta (Aβ) are the major pathological hallmark of Alzheimer’s disease (AD) and have been the primary therapeutic target. Immunotherapies, which are designed to remove brain Aβ deposits, increased levels of soluble Aβ and accelerated brain atrophy in some clinical trials, suggesting that the solubilization of Aβ deposition might facilitate the formation of more toxic Aβ oligomers and enhance neurotoxicity.MethodsThe capacity of antibodies against different epitopes of Aβ to disaggregate preformed Aβ fibrils was investigated. The co-incubation of antibodies and Aβ fibrils was then tested for neurotoxicity both in vitro and in vivo.ResultsAfter the incubation of preformed Aβ fibrils with the N-terminal antibody 6E10, the fibrils were decreased, while the oligomers, mostly dimers and trimers, were significantly increased. However, no such effects were observed for antibodies targeting the middle domain (4G8) and C-terminus of Aβ (8G7). The co-incubates of preformed Aβ fibrils with 6E10 were more neurotoxic, both in vitro and in vivo, than the co-incubates with 4G8 and 8G7.ConclusionsOur results indicate that the antibody targeting the N-terminus of Aβ promoted the transformation of Aβ from fibrils into oligomers and increased neurotoxicity. Immunotherapies should take into consideration the enhanced neurotoxicity associated with the solubilization of Aβ deposits by antibodies against the Nterminus of Aβ.

The relationship between single nucleotide polymorphisms of the NTRK2 gene and sporadic Alzheimer's disease in the Chinese Han population

Alzheimers disease (AD) is characterized by the degeneration of basal forebrain cholinergic neurons, whose survival and function are affected by neurotrophins and their receptors. The impaired signaling pathway of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) is considered to play an important role in AD pathogenesis. To explore the association of polymorphisms within the NTRK2 gene (encoding TrkB) and sporadic AD (sAD), a case-control study was conducted in a Chinese Han cohort including 216 sAD patients and 244 control participants. Five single nucleotide polymorphisms (SNPs), with four of them within the promoter region and one in intron, were selected and genotyped with a polymerase chain reaction-ligase detection reaction (PCR-LDR) method. No association was revealed between these SNPs or the haplotypes containing four promoter SNPs and the risk of sAD. The results of this study indicate that polymorphisms in the selected regions of the NTRK2 gene are unlikely to confer the susceptibility of sAD in the Chinese Han population.

No association of SORT1 gene polymorphism with sporadic Alzheimer's disease in the Chinese Han population.

Increasing evidence shows that sortilin (encoded by SORT1 gene), a member of the vacuolar protein sorting 10 family of sorting receptors, can modulate amyloid-&bgr; peptides (A&bgr;) metabolism and clearance, as well as mediate the neurotoxicity of the A&bgr; oligomer and proneurotrophins, thus playing diverse roles in the pathogenesis of Alzheimer’s disease. To assess the association between single nucleotide polymorphism (SNP) of the SORT1 gene and sporadic Alzheimer’s disease (sAD) in the Chinese Han population, a case–control study was carried out including 220 sAD patients and 245 controls. One tag SNP was selected from the entire SORT1 gene through construction of linkage disequilibrium blocks, and three SNPs located in the vicinity of SORT1 that affect its expression were also selected. The four target SNPs were genotyped using a multiplex PCR-ligase detection reaction method, yielding no significant association between them or haplotypes containing three of them, and the risk of sAD. The results of this study indicate that polymorphisms of the SORT1 gene are unlikely to confer the risk of sAD in the Chinese Han population.

Nutritional Deficiency in Early Life Facilitates Aging-Associated Cognitive Decline

BACKGROUND Nutrition is important for the fetal developmental programming. Nutritional deficiency in early life could increase the susceptibility to many aging-related disorders including cognitive decline. OBJECTIVE Our study aims to investigate the effect of early famine exposure on aging-associated cognitive function. METHODS We recruited 6790 subjects born between 1956 to 1964 during which the Great Chinese Famine occurred (1959-1961). Cognitive function of these subjects were evaluated using the Mini-Mental State Examination (MMSE), the Activities of Daily Living scale (ADL), the Instrumental Activities of Daily Living scale (IADL) and the Clinical Dementia Rating (CDR). RESULTS Our study identified that early exposure to the famine significantly increased the risk of cognitive impairments in later life, leading to higher prevalence of Mild Cognitive Impairment (MCI) and dementia. We also found the sex and rural-urban differences in this malnutrition-induced effect. Illiteracy, history of stroke or diabetes mellitus are great risk factors to facilitate the cognitive decline. CONCLUSION These findings demonstrate that exposure to famine during early life including prenatal period and early childhood facilitates aging-associated cognitive deficits.

Safety and Preliminary Efficacy of Early Tirofiban Treatment After Alteplase in Acute Ischemic Stroke Patients

Background and Purpose— We investigated whether early initiation of tirofiban, a glycoprotein IIb/IIIa antagonist, is safe, can reduce the risk of reocclusion, and improve outcomes in acute ischemic stroke patients after alteplase. Methods— Forty-one patients received alteplase followed by intravenous tirofiban infusion for at least 24 hours. The incidence of symptomatic intracranial hemorrhage, systematic bleedings, and death was recorded. The National Institutes of Health stroke scale score was evaluated at 24 hours and at day 7 (or discharge). Modified Rankin scale was assessed at 3 months. Outcomes for these patients were compared with a propensity score–matched historical cohort with alteplase only. Results— The incidence of symptomatic intracranial hemorrhage, death, or systematic bleedings (P=1.00) was not increased in the alteplase/tirofiban group. At 24 hours, fewer patients experienced reocclusion in the alteplase/tirofiban group (2.4% versus 22.0%; P=0.025). At day 7 or discharge, the median National Institutes of Health stroke scale score was significantly lower in the alteplase/tirofiban group (1 versus 6; P=0.002). At 3 months, more patients had favorable outcomes of modified Rankin scale 0 to 1 (70.7% versus 46.2%; P=0.026). Conclusions— Intravenous tirofiban immediately after alteplase seems to be safe and potentially more effective when compared with alteplase alone for selected stroke patients. Clinical Trial Registration— URL: http://www.chictr.org.cn/. Unique identifier: ChiCTR-TRC-14004630.

Identification of a Novel Mutation in the Presenilin 1 Gene in a Chinese Alzheimer’s Disease Family

This study has identified a gene mutation in a Chinese family with Alzheimer’s disease (AD). Family members were screened by a set of medical examinations and neuropsychological tests. Their DNA was extracted from blood cells and sequenced for gene mutation in the amyloid precursor protein (APP), the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Clinical manifestation of these patients included memory loss, counting difficulty, personality change, disorientation, dyscalculia, agnosia, aphasia, and apraxia, which was similar to that of the familial AD (FAD) patients harboring other PS1 mutations. We intend to add a novel mutation F105C of the PS1 gene to the pool of FAD mutations. With the current available genetic data, mutations of the PS1 gene account for the majority of gene mutations in Chinese FAD.

Safety and preliminary efficacy of intravenous tirofiban in acute ischemic stroke patient without arterial occlusion on neurovascular imaging studies

BACKGROUND There has been no effective treatment for acute ischemic stroke (AIS) patients who presented to the Emergency Department >4.5h without a visible arterial occlusion on the neurovascular imaging studies. In this study, we aimed to investigate whether intravenous antiplatelet agent tirofiban was safe and potentially effective in AIS patients who had no visible arterial occlusion and was outside of treatment window for Alteplase. The goal of this study was to collect preliminary data to plan a future phase II study. METHOD Twenty-five patients received intravenous tirofiban therapy. The safety outcomes were assessed by the incidence of symptomatic intracerebral hemorrhage (sICH), systematic bleeding and mortality. Efficacy outcomes were evaluated with National Institutes of Health Stroke Scale (NIHSS) score at day 7 (or discharge) and modified Rankin Scale (mRS) at 90days. Outcomes for these patients were compared with a historical age-gender-admission-NIHSS matched cohort treated with aspirin and/or clopidogrel. RESULTS The rate of intracerebral hemorrhage, systematic bleedings, and death were not found in both groups. At day 7 or discharge, the neurological function improved significantly in both treatment groups. However, the NIHSS score was lower in tirofiban group compared with the control group (2 vs.3, p=0.045). At 3months, more patients in tirofiban group had favorable outcomes (mRS 0-1) compared with control group (84% vs. 52%; adjusted odds ratio: 10.57; 95% CI: 1.54-72.33; p=0.016). CONCLUSIONS Intravenous tirofiban appears to be safe and potentially effective for the ischemic stroke patients with no artery occlusion on neurovascular imaging studies and being out of the window for thrombolytic therapy. A next logic step is to plan for a phase II study.