|The team led by Ding Jian Qing and Chen Sheng Di from Ruijin hospital made major progress in the pathogenesis of alzheimer's disease|
On April 11, The Journal of Clinical Investigation published an academic paper online, titled “Amyloid precursor protein-mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration,”. The paper is completed by ding jian qing and chen sheng di from the department of neurology and institute of neurology in rui jin hospital affiliated to shanghai jiao tong university school of medicine with a joint research team at The university of California, San Diego, neural science lab led by professor Wu Cheng Biao together in the completion of this study. The research has for the first time, explained the Alzheimer‘s disease, (Alzheimer’s diseases, AD) of Nerve growth factor (Nerve growth factor, model NGF) and the molecular mechanisms of axons reverse transportation anomaly.
At present, the aging of world‘s population leads to a marked increase in the incidence of AD, which has become one of the main threats to harm human health. It is expected in 2050, the world will meet the problem of having an AD patient out of every 85 people. With respect to the social and economic factors to the families, it has brought a huge impact and burden on those who suffer from this disease. Normal human brain associated with memory structure is mainly in the cerebral cortex, hippocampus and basal forebrain cholinergic nervous system. Among them, the basal forebrain cholinergic nervous system is a valid can maintain brain bladder alkali concentration of neurotransmitters, determining one important structure of normal memory and intelligence. And the NGF plays an important role in maintaining the basal forebrain cholinergic neuron survival and normal function plays an important role in normal state. The NGF plays in neuronal axons synapse and its receptor TrkA combination, forming a model NGF signal after endocytosis. This signal travels along the axon reverse transportation, through in the early, late in transit to the neuron cell body and further activates the downstream pathway, PI3K, Erk signal, so as to maintain the survival of the neurons and normal function. Existing studies have found that the AD in the basal forebrain cholinergic neurons appeared early atrophy, degeneration and death associated with abnormal model NGF signal to reduce production, but model NGF signal abnormal changes of specific molecular mechanism has not yet clear.
Under the guidance of professor ding jian qing and professor Wu Cheng biao from ruijin hospital affiliated to shanghai jiao tong university school of medicine department of neurology, attending physician Xu Wei, goes deep into the research of NGF’s role in alzheimer‘s disease molecular mechanism of abnormal signal transmission in the thorough research. The results suggest that in the early AD, the amyloid precursor protein (APP) and its metabolites beta carboxyl terminal fragment (beta CTF, C99) can lead to a small G proteins (small GTPases) Rab5 activity increased. Rab5 is an early marker of inner body in cell body system proteins, and early on the formation of the inner body, the fusion, the activity of the abnormal increase can lead to abnormal fusion of early inner body and the abnormal increase of volume, thus influence the signal of NGF plays in neuronal axons reverse transportation; The study also found, on the application of Rab5 dominant negative mutant - Rab5S34N inhibition induced by APP or C99 Rab5 abnormalities after activation, signal model NGF in axons reverse transport abnormalities were improved significantly. The results also confirmed in the animal model of fruit flies. In this study, it has for the first time confirmed that the AD model NGF may be the mechanism of abnormal signal axon reverse transportation induced by abnormal accumulation of APP or C99 Rab5 caused by abnormal activation; At the same time, this study established the original generation of basal forebrain cholinergic neurons cultivation system and NGF plays in neuronal axons reverse transport dynamic observation system which will also be the future research important platform to the pathogenesis of alzheimer’s disease.
The neurology department of rui jin hospital affiliated to shanghai jiao tong university school of medicine, and institute of neurology, under the guidance and leadership of professor ding jian qing and professor chen sheng di, has a long-term commitment to alzheimer‘s disease clinical and basic research, hopes to find the clinical diagnosis and treatment related biomarkers and drug targets. Effectively, their study as a kind of new drug targets for Rab5 the possibility of treatment for alzheimer’s disease provides strong experimental basis.
The Research backed by the national natural science Foundation, ministry of science and technology of national key basic Research development program, as well as science and technology commission of Shanghai “scientific and technological innovation action plan is based on project as well as the NIH funds and LuMind Research Down Syndrome Foundation funds.