Small molecule modulation of the p75 neurotrophin receptor suppresses age- and genotype-associated neurodegeneration in HIV gp120 transgenic mice.
Small molecule modulation of the p75 neurotrophin receptor suppresses age- and genotype-associated neurodegeneration in HIV gp120 transgenic mice.
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DOI：
10.1016/j.expneurol.2020.113489
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发表时间：
2021-01
影响因子：
5.3
通讯作者：
Meeker RB
中科院分区：
文献类型：
--
作者：
Xie Y;Seawell J;Boesch E;Allen L;Suchy A;Longo FM;Meeker RB
艾滋病毒在中枢神经系统中的持续存在导致高达50%的艾滋病毒感染者出现认知缺陷，即使通过抗逆转录病毒治疗进行全身抑制。慢性炎症与年龄相关性变性的相互作用使这些个体加速衰老和其他神经退行性疾病的风险增加，并且没有有效阻止这些过程的治疗方法。衰老和炎症的副作用可能部分由p75神经营养因子受体（p75 NTR）表达的增加介导，p75神经营养因子受体（p75 NTR）表达的增加使神经营养因子信号传导的平衡向保护性较小的途径转移。为了确定p75 NTR的调节是否可以改变疾病过程，我们用设计用于接合p75 NTR并下调退行性信号的小分子配体处理HIV gp 120转基因小鼠。每天用50 mg/kg LM 11 A-31治疗4个月抑制了小胶质细胞的年龄和基因型依赖性活化，减少了p75 NTR的表达，增加了微管相关蛋白-2（MAP-2），减少了树突状血管曲张，并减缓了海马中小清蛋白免疫反应性神经元的损失。在海马中共表达p75 NTR的细胞外簇中鉴定了微管相关蛋白Tau的年龄相关积累，表明Tau和p75 NTR之间的联系。尽管p75 NTR和Tau之间关系的意义尚不清楚，但随着gp 120小鼠进入老年（>16个月），Tau-1免疫反应性降低，表明Tau可能转变为更多的病理学修饰;这一过程被LM 11 A-31阻断。总体而言，LM 11 A-31的作用与具有显著治疗潜力的强神经保护和抗炎作用一致。
The persistence of HIV in the central nervous system leads to cognitive deficits in up to 50% of people living with HIV even with systemic suppression by antiretroviral treatment. The interaction of chronic inflammation with age-associated degeneration places these individuals at increased risk of accelerated aging and other neurodegenerative diseases and no treatments are available that effectively halt these processes. The adverse effects of aging and inflammation may be mediated, in part, by an increase in the expression of the p75 neurotrophin receptor (p75NTR) which shifts the balance of neurotrophin signaling toward less protective pathways. To determine if modulation of p75NTR could modify the disease process, we treated HIV gp120 transgenic mice with a small molecule ligand designed to engage p75NTR and downregulate degenerative signaling. Daily treatment with 50 mg/kg LM11A-31 for 4 months suppressed age- and genotype-dependent activation of microglia, reduced expression of p75NTR, increased microtubule associated protein-2 (MAP-2), reduced dendritic varicosities and slowed the loss of parvalbumin immunoreactive neurons in the hippocampus. An age related accumulation of microtubule associated protein Tau was identified in the hippocampus in extracellular clusters that co-expressed p75NTR suggesting a link between Tau and p75NTR. Although the significance of the relationship between p75NTR and Tau is unclear, a decrease in Tau-1 immunoreactivity as gp120 mice entered old age (>16 months) suggests that the Tau may transition to more pathological modifications; a process blocked by LM11A-31. Overall, the effects of LM11A-31 are consistent with strong neuroprotective and anti-inflammatory actions that have significant therapeutic potential.
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影响因子：
3.3
作者：
Dawson, H. N.;Cantillana, V.;Jansen, M.;Wang, H.;Vitek, M. P.;Wilcock, D. M.;Lynch, J. R.;Laskowitz, D. T.
通讯作者：
Laskowitz, D. T.
影响因子：
3
作者：
Capsoni, S.;Brandi, R.;Cattaneo, A.
通讯作者：
Cattaneo, A.
影响因子：
16.2
作者：
Amilhon, Benedicte;Huh, Carey Y. L.;Williams, Sylvain
通讯作者：
Williams, Sylvain
影响因子：
6.1
作者：
Bragg, DC;Boles, JC;Meeker, RB
通讯作者：
Meeker, RB
影响因子：
3.4
作者：
Al-Shawi, Raya;Hafner, Angela;Cowen, Timothy
通讯作者：
Cowen, Timothy