Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA and Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD 21205, USA.
Nanoscale. 2021 Jan 21;13(2):939-952. doi: 10.1039/d0nr05958g.
Switching microglia from a disease exacerbating, 'pro-inflammatory' state into a neuroprotective, 'anti-inflammatory' phenotype is a promising strategy for addressing multiple neurodegenerative diseases. Pro-inflammatory microglia contribute to disease progression by releasing neurotoxic substances and accelerating pathogenic protein accumulation. PPARα and PPARγ agonists have both been shown to shift microglia from a pro-inflammatory ('M1-like') to an alternatively activated ('M2-like') phenotype. Such strategies have been explored in clinical trials for neurological diseases, such as Alzheimer's and Parkinson's disease, but have likely failed due to their poor blood-brain barrier (BBB) penetration. Hydroxyl-terminated polyamidoamine dendrimers (without the attachment of any targeting ligands) have been shown to cross the impaired BBB at the site of neuroinflammation and accumulate in activated microglia. Therefore, dendrimer conjugation of a PPARα/γ dual agonist may enable targeted phenotype switching of activated microglia. Here we present the synthesis and characterization of a novel dendrimer-PPARα/γ dual agonist conjugate (D-tesaglitazar). In vitro, D-tesaglitazar induces an 'M1 to M2' phenotype shift, decreases secretion of reactive oxygen species, increases expression of genes for phagocytosis and enzymatic degradation of pathogenic proteins (e.g. β-amyloid, α-synuclein), and increases β-amyloid phagocytosis. These results support further development of D-tesaglitazar towards translation for multiple neurodegenerative diseases, especially Alzheimer's and Parkinson's Disease.
将小胶质细胞从促病加重的“促炎”状态转变为神经保护的“抗炎”表型是治疗多种神经退行性疾病的一种有前途的策略。促炎小胶质细胞通过释放神经毒性物质和加速致病蛋白积累，促进疾病进展。过氧化物酶体增殖物激活受体α（PPARα）和过氧化物酶体增殖物激活受体γ（PPARγ）激动剂都已被证明可以使小胶质细胞从促炎（“M1 样”）表型转变为另一种激活的（“M2 样”）表型。这些策略已在针对神经退行性疾病（如阿尔茨海默病和帕金森病）的临床试验中进行了探索，但由于其血脑屏障（BBB）通透性差，可能已经失败。羟基化聚酰胺胺树枝状大分子（无任何靶向配体连接）已被证明可以穿过神经炎症部位受损的 BBB，并在激活的小胶质细胞中积累。因此，PPARα/γ 双重激动剂的树枝状大分子缀合可能使激活的小胶质细胞实现靶向表型转换。在这里，我们提出了一种新型树枝状大分子-PPARα/γ 双重激动剂缀合物（D-tesaglitazar）的合成和表征。在体外，D-tesaglitazar 诱导“M1 向 M2”表型转变，减少活性氧物质的分泌，增加吞噬和酶降解致病蛋白（如β-淀粉样蛋白、α-突触核蛋白）的基因表达，并增加β-淀粉样蛋白的吞噬作用。这些结果支持进一步开发 D-tesaglitazar 以用于多种神经退行性疾病的转化，特别是阿尔茨海默病和帕金森病。
