The Expression Of P75NTR In The Brain Of Alzheimer’s Disease And Interaction Sites Between P75NTR And Aβ

Background and aimsAlzheimer’s Disease is the most common dementia among the elderly. The loss ofcortical and hippocampal neurons, particularly the basal forebrain cholinergic neurons(cBF),senile plaques containing amyloid-beta(Aβ) and hyperphosphorylated tau neurofibrillarytangles are the main pathological features of AD. A progressive loss of cognitive functions,particularly memory, is the main clinical manifestation. Aβ is the key pathogenic factor, andits misfolding and deposition form senile plaque, which is one of the most importantpathological marks. The p75neurotrophin receptor(p75NTR) was reported for the first timeas a nerve growth factor receptor(NGFR). Subsequent studies found that p75NTR is a low-affinity pan-neurotrophin receptor, which can bind with not only NGF but brain-derivedneurotrophic factor(BDNF),Neurotrophin-3(NT-3),Neurotrophin-4/5(NT-4/5) and theirprecursors(pro-NGF,pro-BDNF,pro-NT-3, pro-NT-4/5). The expression level of p75NTR isvery low under physiological conditions, and it mainly located in cBF and blood vessels ofthe brain. p75NTR was observed in some affected neurons as well under pathologicalconditions. Our preliminary data showed that p75NTR is up-regulated in the brain ofAPPswe/PS1dE9transgenic mice and may regulate the production and deposition of Aβ. Wealso found that p75NTR positive degenerative neurites always colocalize with senile plaques.However, the expression level of p75NTR in AD patients’ brain, the association of p75NTRand senile plaques and interaction sites between p75NTR and Aβ remain to be explored.Therefore, we performed these two studies based on the previous evidence:(1) quantifiedlevels of p75NTR in the brain of AD patients and AD transgenic mice, and further analyzedthe spatial relationship of p75NTR and senile plaques.(2) investigated specific interactionsites between p75NTR and Aβ by ThT Assay and Co-immunoprecipitation. Materials and methods1. Western Blot was conducted to quantify the2expression levels of p75NTR in ADpatients, AD transgenic mice and their normal controls; the distribution of p75NTR in thebrain of AD patients, AD transgenic mice and their normal controls; and the spatialrelationship of p75NTR and senile plaques were analyzed by Immunohistochemistry.2. Detect the effects of p75NTR-Cysteine Rich Domain1-2(p75NTR-CRD1-2), p75NTR-CRD2-3, p75NTR-CRD3-4and p75NTR-ECD on Aβ aggregation by ThT Assay; investigatespecific interaction sites between p75NTR and Aβ by Co-immunoprecipitation.Results1. Compared with normal controls, the expression levels of p75NTR in AD patients andAD transgenic mice are up-regulated and the p75NTR positive degenerative fibers located inthe center of senile plaques.2. Specific interaction sites between p75NTR and Aβ are the second cysteine-richdomain(CRD2) and the forth cysteine-rich domain(CRD4).Conclusions1. The level of p75NTR is increased in AD brain and p75NTR positive neurofibrilslocated in the core of senile plaques, suggesting that p75NTR may play an important role inthe plaque formation.2. p75NTR-CRD2and p75NTR-CRD4can interact with Aβ, making it a putativetherapeutic target.