Niemann-Pick disease type C（NPC） is a fatal, neurovisceral lipid storage disease, neuropathologically characterized by cytoplasmic sequestration of glycolipids in neurons, progressive neuronal loss, neurofibrillary tangles（NFTs） formation, and axonal spheroids（AS）. Cytoskeletal pathology including accumulation of hyperphosphorylated cytoskeletal proteins is a neuropathological hallmark of the mouse model of NPC（npc mice）. With a goal of elucidating the mechanisms underlying the lesion formation, we investigated the temporal and spatial characteristics of cytoskeletal lesions and the roles of cdc2, cdk4, and cdk5 in lesion formation in young npc mice. Cytoskeletal lesions were detectable in npc mice at three weeks of age. Importantly, concomitant activation of cdc2/cyclin B1 kinase and accumulation of a subsequently generated cohort of phospho-epitopes were detected. The activation of cdk4/cyclin D1 and cdk5/p25 kinases was observed during the fourth week of life in npc mice, and this activation contributed to the lesion formation. We concluded that the progression of cytoskeletal pathology in npc mice older than four weeks is accelerated by the cumulative effect of cdc2, cdk4, and cdk5 activation. Furthermore, cdc2/cyclin B1 may act as a key initial player one week earlier. Targeting cell cycle activation may be beneficial to slow down the NPC pathogenesis.
Background：Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer＇s disease （AD）.Dysregulation of the endosomal-autophagic-lysosomal （EAL） pathway,which impairs amyloid precursor protein processing,is one of the earliest changes in AD.However,the precise role of EAL pathway in neurodegeneration remains unclear.This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction.Methods：We used 3-,7-,and 12-month-old APPswe/PSEN1dE9 （APP/PS1） mice to model different stages of AD with age-and gender-matched wild-type littermates as controls （4-7 mice per group） and detected the changes of EAL markers,endosomal organizers Rab5 and Rab7,autophagosome marker LC3B,and lysosomal proteins Lamp 1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis.To further explore the mechanism of EAL dysregulation in AD,components of the class Ⅲ phosphatidylinositol 3-kinase （PI3KC3） complex,activators ofRab7 （Beclin1 and UVRAG）,and the negative regulator of Rab7 （Rubicon） were also measured in this two brain regions.Results：In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly,EAL pathway,and related PI3KC3 members,UVRAG and Beclin1 were upregulated both in cortex and hippocampus （all P 〈 0.05）.By the age of 12 months old,when abundant amyloid plaques formed,EAL markers,UVRAG,and Beclin 1 were also upregulated in the cortex （all P 〈 0.05）.However,Rab7 was decreased significantly （P =0.0447）,accompanied by a reduction of its activating PI3KC complex component Beclin1 （P =0.0215） and enhancement of its inhibiting component Rubicon （P =0.0055） in the hippocampus.Conclusions：Our study implies that EAL pathway,represented as Rab7 and its PI3KC3 regulators＇ expressions,showed temporal and spatial variation in brains at different stages of AD.It provides new insights into the role of EAL pathway in pathogenesis and indicates pot
Li BaXiao-Hua ChenYan-Lin ChenQing NieZhi-Jun LiFeng-Fei DingMin Zhang
