PAC1 receptor-mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain.
PAC1 receptor-mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain.
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DOI：
10.1126/scitranslmed.aba7394
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发表时间：
2021-05-26
影响因子：
17.1
通讯作者：
Myeku N
中科院分区：
文献类型：
--
作者：
Schaler AW;Runyan AM;Clelland CL;Sydney EJ;Fowler SL;Figueroa HY;Shioda S;Santa-Maria I;Duff KE;Myeku N
在突触中的病理tau的积累已被确定为阿尔茨海默氏病（AD）的早期事件，与AD患者的认知下降相关。由于神经元内的遗漏，神经元之间的跨性别转移或使用大脑的亚细胞分馏。 RTG4510 TAU转基因小鼠的组织与AD患者的人体脑组织，我们发现，在突触后隔室中积累了种子能力的Tau，这主要在突触后腔内介导的毒性在突触后的毒性中被损害的蛋白酶隔离而恶化。针对蛋白酶体降解的蛋白质的多泛素化。 RTG4510小鼠大脑的隔室刺激了垂体腺苷酸环化酶激活多肽（PACAP）1型受体（PAC1R）及其配体PACAP的室内室内室内给予RTG4510小鼠。 PACAP处理后的小鼠大脑。 RTG4510转基因小鼠在两个行为测试中的认知性能提高。
Accumulation of pathological tau in synapses has been identified as an early event in Alzheimer’s disease (AD) and correlates with cognitive decline in patients with AD. Tau is a cytosolic axonal protein, but under disease conditions, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, we found accumulation of seed-competent tau predominantly in postsynaptic compartments. Tau-mediated toxicity in postsynaptic compartments was exacerbated by impaired proteasome activity detected by measuring lysine-48 polyubiquitination of proteins targeted for proteasomal degradation. To combat the accumulation of tau and proteasome impairment in the postsynaptic compartments of rTg4510 mouse brain, we stimulated the pituitary adenylate cyclase–activating polypeptide (PACAP) type 1 receptor (PAC1R) with its ligand PACAP administered intracerebroventricularly to rTg4510 mice. We observed enhanced synaptic prote- asome activity and reduced total tau in postsynaptic compartments in mouse brain after PACAP treatment. The clearance of tau from postsynaptic compartments correlated with attenuated tauopathy and improved cognitive performance of rTg4510 transgenic mice on two behavioral tests. These results suggest that activating PAC1R could prevent accumulation of aggregate-prone tau and indicate a potential therapeutic approach for AD and other tauopathies.
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影响因子：
4.3
作者：
DeVos SL;Corjuc BT;Oakley DH;Nobuhara CK;Bannon RN;Chase A;Commins C;Gonzalez JA;Dooley PM;Frosch MP;Hyman BT
通讯作者：
Hyman BT
DOI：
10.1186/s10194-018-0855-1
发表时间：
2018-04-04
期刊：
The journal of headache and pain
影响因子：
--
作者：
Hirabayashi T;Nakamachi T;Shioda S
通讯作者：
Shioda S
位点特异性蛋白酶体磷酸化控制细胞增殖和肿瘤发生。
影响因子：
21.3
作者：
Guo X;Wang X;Wang Z;Banerjee S;Yang J;Huang L;Dixon JE
通讯作者：
Dixon JE
来自阿尔茨海默氏症大脑的独特病理tau构象体传播了非转基因小鼠的tau病理。
DOI：
10.1084/jem.20160833
发表时间：
2016-11-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guo JL;Narasimhan S;Changolkar L;He Z;Stieber A;Zhang B;Gathagan RJ;Iba M;McBride JD;Trojanowski JQ;Lee VM
通讯作者：
Lee VM
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi