A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes.
A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes.
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DOI：
10.1016/j.nbd.2023.106196
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发表时间：
2023-08
影响因子：
6.1
通讯作者：
Leak RK
中科院分区：
文献类型：
--
作者：
Bhatia TN;Jamenis AS;Abbas M;Clark RN;Miner KM;Chandwani MN;Kim RE;Hilinski W;O'Donnell LA;Luk KC;Shi Y;Hu X;Chen J;Brodsky JL;Leak RK
随着年龄增长以及在路易体疾病中（包括帕金森病患者的嗅球内）都能观察到反应性小胶质细胞。然而，小胶质细胞在这些疾病中的功能影响仍存在争议。通过集落刺激因子1受体（CSF1R）抑制剂PLX5622的短期饮食脉冲来重置这些反应性细胞可能对治疗路易体相关病理具有潜在作用。据我们所知，短期暴露后撤回PLX5622在预先形成的α - 突触核蛋白纤维（PFF）模型中尚未进行测试，包括在两性老年小鼠中。与老年雌性小鼠相比，我们报告称，在将PFFs注射到后嗅球后，采用对照饮食的老年雄性小鼠在边缘嗅脑中有更多的磷酸化α - 突触核蛋白 + 包涵体。然而，与雄性相比，老年雌性小鼠的包涵体尺寸更大。短期（14天）饮食摄入PLX5622后再给予对照食物，可减少老年雄性小鼠（而非雌性）的包涵体数量和不溶性α - 突触核蛋白水平，并且出乎意料地增加了两性的包涵体尺寸。PLX5622的短暂给药还改善了注射PFF的老年小鼠的空间参考记忆，这在Y迷宫中表现为进入新臂的次数增加。良好的记忆与包涵体尺寸呈正相关，与包涵体数量呈负相关。尽管我们提醒必须在α - 突触核蛋白病模型中进一步测试PLX5622的给药情况，但我们的数据表明，在注射PFF的老年小鼠中，尺寸较大但数量较少的α - 突触核蛋白病变结构与更好的神经学结果相关。
Reactive microglia are observed with aging and in Lewy body disorders, including within the olfactory bulb of men with Parkinson’s disease. However, the functional impact of microglia in these disorders is still debated. Resetting these reactive cells by a brief dietary pulse of the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 may hold therapeutic potential against Lewy-related pathologies. To our knowledge, withdrawal of PLX5622 after short-term exposure has not been tested in the preformed α-synuclein fibril (PFF) model, including in aged mice of both sexes. Compared to aged female mice, we report that aged males on the control diet showed higher numbers of phosphorylated α-synuclein+ inclusions in the limbic rhinencephalon after PFFs were injected in the posterior olfactory bulb. However, aged females displayed larger inclusion sizes compared to males. Short-term (14-day) dietary exposure to PLX5622 followed by control chow reduced inclusion numbers and levels of insoluble α-synuclein in aged males—but not females—and unexpectedly raised inclusion sizes in both sexes. Transient delivery of PLX5622 also improved spatial reference memory in PFF-infused aged mice, as evidenced by an increase in novel arm entries in a Y-maze. Superior memory was positively correlated with inclusion sizes but negatively correlated with inclusion numbers. Although we caution that PLX5622 delivery must be tested further in models of α-synucleinopathy, our data suggest that larger-sized—but fewer—α-synucleinopathic structures are associated with better neurological outcomes in PFF-infused aged mice.
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影响因子：
7.1
作者：
Bachstetter AD;Van Eldik LJ;Schmitt FA;Neltner JH;Ighodaro ET;Webster SJ;Patel E;Abner EL;Kryscio RJ;Nelson PT
通讯作者：
Nelson PT
影响因子：
15.1
作者：
Barth M;Bacioglu M;Schwarz N;Novotny R;Brandes J;Welzer M;Mazzitelli S;Häsler LM;Schweighauser M;Wuttke TV;Kronenberg-Versteeg D;Fog K;Ambjørn M;Alik A;Melki R;Kahle PJ;Shimshek DR;Koch H;Jucker M;Tanriöver G
通讯作者：
Tanriöver G
影响因子：
5.6
作者：
Klusa VZ;Isajevs S;Svirina D;Pupure J;Beitnere U;Rumaks J;Svirskis S;Jansone B;Dzirkale Z;Muceniece R;Kalvinsh I;Vinters HV
通讯作者：
Vinters HV
影响因子：
15.1
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
通讯作者：
McLean PJ
影响因子：
12.7
作者：
Attems J;Toledo JB;Walker L;Gelpi E;Gentleman S;Halliday G;Hortobagyi T;Jellinger K;Kovacs GG;Lee EB;Love S;McAleese KE;Nelson PT;Neumann M;Parkkinen L;Polvikoski T;Sikorska B;Smith C;Grinberg LT;Thal DR;Trojanowski JQ;McKeith IG
通讯作者：
McKeith IG