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.
Alzheimer's disease
Dementia
Episodic memory
Insulin resistance
Leptin peptides
Neurodegeneration
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
02
03
2020
revised:
07
07
2020
accepted:
21
07
2020
pubmed:
2
8
2020
medline:
5
1
2021
entrez:
2
8
2020
Statut:
ppublish
Résumé
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.
Sections du résumé
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
GENERAL SIGNIFICANCE
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.
Identifiants
pubmed: 32738275
pii: S0304-4165(20)30209-9
doi: 10.1016/j.bbagen.2020.129697
pmc: PMC7484172
mid: NIHMS1616074
pii:
doi:
Substances chimiques
Blood Glucose
0
Leptin
0
Neuroprotective Agents
0
Peptides
0
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
129697Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL136706
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest None.
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