MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, improves episodic memory, and reduces serum levels of tumor necrosis factor-alpha and neurodegeneration in mouse models of Type 1 and Type 2 Diabetes Mellitus

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 11; p. 129697
• Main Authors: Hirschstein, Zall, Vanga, Gautam Reddy, Wang, Guirong, Novakovic, Zachary M., Grasso, Patricia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2020
• Subjects: Alzheimer's disease; Animals; Blood Glucose - analysis; Dementia; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Disease Models, Animal; Episodic memory; Humans; Insulin Resistance; Leptin - analogs & derivatives; Leptin - therapeutic use; Leptin peptides; Male; Memory, Episodic; Mice; Neurodegeneration; Neuroprotective Agents - chemistry; Neuroprotective Agents - therapeutic use; Peptides - chemistry; Peptides - therapeutic use; Tumor Necrosis Factor-alpha - blood; Insulin resistance; Leptin peptides; Neurodegeneration; Alzheimer's disease; Episodic memory; Dementia
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129697

Extracellular beta-amyloid (Aβ), intra-neuronal hyper-phosphorylated tau protein, and chronic inflammation are neuropathological hallmarks of Alzheimer's Disease (AD). A link between AD, insulin dysfunction, and tumor necrosis factor-alpha (TNF-α) in promoting both tau and Aβ pathologies in vivo has been proposed. MA-[D-Leu-4]-OB3 was given, with or without insulin, to streptozotocin (STZ)-treated male Swiss Webster mice, and to male diet-induced obese (DIO) mice. Brains were excised, and coronal sections were imaged with fluoro jade-C (FJC), thioflavin-S, or hematoxylin and eosin (H&E). Serum TNF-α and IGF-1 were measured by ELISA. Histopathological changes in the cerebral cortex (CC) and hippocampus (HC) were correlated with changes in glycemic regulation, episodic memory, and serum levels of TNF-α and IGF-1. In STZ-treated mice, blood glucose and serum TNF-α and IGF-1 were reduced by insulin alone, and normalized when MA-[D-Leu-4]-OB3 was given in combination with insulin. Improvement in episodic memory was inversely correlated with the number of FJC-positive cells in the CC and HC and serum TNF-α and IGF-1. FJC, thioflavin-S and H&E staining indicated no Aβ deposition. Similar results were observed in DIO mice treated with MA-[D-Leu-4]-OB3. The mechanism by which MA-[D-Leu-4]-OB3 improves episodic memory in mouse models of TIDM and T2DM appears to be related to improved insulin sensitivity and reduced TNF-α-induced neurodegeneration. MA-[D-Leu-4]-OB3 may have application to human pre-clinical and clinical AD and AD-like dementia by interrupting the cascade of insulin resistance, neuro-inflammation, and neurodegeneration, that characterizes these diseases. •MA-[D-Leu-4]-OB3 reduces neurodegeneration in mouse models of T1DM and T2DM.•MA-[D-Leu-4]-OB3 reduces serum TNF-α and IFG-1 in mouse models of T1DM and T2DM.•MA-[D-Leu-4]-OB3 improves cognitive function in mouse models of T1DM and T2DM.•MA-[D-Leu-4]-OB3 may have application to human AD, VaD, or mixed dementia.