Engel Matthew G, Narayan Sushma, Cui Min-Hui, Branch Craig A, Zhang Xusheng, Gandy Samuel E, Ehrlich Michelle, Huffman Derek M
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.
J Alzheimers Dis. 2025 Jan;103(1):113-126. doi: 10.1177/13872877241299056. Epub 2024 Nov 29.
Insulin-like growth factor-1 (IGF-1) promotes neurogenesis, cell survival, and glial function, making it a promising candidate therapy in Alzheimer's disease (AD).
Long arginine 3-IGF-1 (LR3-IGF-1) is a potent IGF-1 analogue. We sought to determine whether intranasal (IN) LR3 treatment would delay cognitive decline and pathology in 5XFAD mice.
Wildtype and 5XFAD male mice were treated for 7 months (3-10 months of age), with IN LR3-IGF-1 or IN Vehicle (Veh) (n = 19-27 mice/group). Behavior, memory, and brain imaging were assessed at 8-9 months of age and tissues collected at 10 months. A comprehensive amyloid-β (Aβ) profile and other pathologic features were conducted and supportive stimulation studies in BV-2 microglial cells were also performed.
In male 5XFAD mice, IN LR3-IGF-1 treatment improved body composition, but did not significantly alter cognitive symptoms, as assessed by multiple assays. In cortex, LR3 treatment improved some facets of pathology, including a reduction in filamentous plaques, and increase in inert plaques, corresponding with a reduction in low molecular weight Aβ oligomers. , uptake of Aβ peptide by BV2 cells was enhanced by LR3-IGF-1, which was also found to promote gene pathways implicated in actin remodeling and endocytosis.
LR3 promotes favorable effects on Aβ plaque remodeling in cortex of male 5XFAD mice but fails to preserve aspects of behavior or memory. While these data do not support LR3 as a monotherapy , they do warrant further investigation into its potential for combinatorial formulations aimed at targeting the complexity of AD.
胰岛素样生长因子-1（IGF-1）可促进神经发生、细胞存活和神经胶质功能，使其成为阿尔茨海默病（AD）中一种有前景的候选治疗方法。
长精氨酸3-IGF-1（LR3-IGF-1）是一种有效的IGF-1类似物。我们试图确定鼻内（IN）给予LR3治疗是否会延缓5XFAD小鼠的认知衰退和病理变化。
野生型和5XFAD雄性小鼠在3至10月龄时接受7个月的鼻内LR3-IGF-1或鼻内载体（Veh）治疗（每组n = 19 - 27只小鼠）。在8至9月龄时评估行为、记忆和脑成像，并在10月龄时收集组织。进行了全面的淀粉样β蛋白（Aβ）分析和其他病理特征分析，还在BV-2小胶质细胞中进行了支持性刺激研究。
在雄性5XFAD小鼠中，通过多种检测方法评估，鼻内给予LR3-IGF-1治疗改善了身体组成，但未显著改变认知症状。在皮质中，LR3治疗改善了一些病理方面，包括丝状斑块减少、惰性斑块增加，相应地低分子量Aβ寡聚体减少。LR3-IGF-1增强了BV2细胞对Aβ肽的摄取，还发现其促进了与肌动蛋白重塑和内吞作用相关的基因途径。
LR3对雄性5XFAD小鼠皮质中的Aβ斑块重塑有有利影响，但未能保留行为或记忆方面。虽然这些数据不支持将LR3作为单一疗法，但确实值得进一步研究其在针对AD复杂性的联合制剂中的潜力。
