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The Medial Septum Is Insulin Resistant in the AD Presymptomatic Phase: Rescue by Nerve Growth Factor-Driven IRS 1 Activation.
- Source :
-
Molecular neurobiology [Mol Neurobiol] 2019 Jan; Vol. 56 (1), pp. 535-552. Date of Electronic Publication: 2018 May 07. - Publication Year :
- 2019
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Abstract
- Basal forebrain cholinergic neurons (BFCN) are key modulators of learning and memory and are high energy-demanding neurons. Impaired neuronal metabolism and reduced insulin signaling, known as insulin resistance, has been reported in the early phase of Alzheimer's disease (AD), which has been suggested to be "Type 3 Diabetes." We hypothesized that BFCN may develop insulin resistance and their consequent failure represents one of the earliest event in AD. We found that a condition reminiscent of insulin resistance occurs in the medial septum of 3 months old 3×Tg-AD mice, reported to develop typical AD histopathology and cognitive deficits in adulthood. Further, we obtained insulin resistant BFCN by culturing them with high insulin concentrations. By means of these paradigms, we observed that nerve growth factor (NGF) reduces insulin resistance in vitro and in vivo. NGF activates the insulin receptor substrate 1 (IRS <subscript>1</subscript> ) and rescues c-Fos expression and glucose metabolism. This effect involves binding of activated IRS <subscript>1</subscript> to the NGF receptor TrkA, and is lost in presence of the specific IRS inhibitor NT157. Overall, our findings indicate that, in a well-established animal model of AD, the medial septum develops insulin resistance several months before it is detectable in the neocortex and hippocampus. Remarkably, NGF counteracts molecular alterations downstream of insulin-resistant receptor and its nasal administration restores insulin signaling in 3×Tg-AD mice by TrkA/IRS <subscript>1</subscript> activation. The cross-talk between NGF and insulin pathways downstream the insulin receptor suggests novel potential therapeutic targets to slow cognitive decline in AD and diabetes-related brain insulin resistance.
- Subjects :
- Alzheimer Disease genetics
Animals
Cholinergic Neurons drug effects
Cholinergic Neurons metabolism
Disease Models, Animal
Mice
Mice, Transgenic
Phosphorylation drug effects
Rats
Rats, Wistar
Receptor, Insulin metabolism
Septal Nuclei drug effects
Signal Transduction drug effects
Signal Transduction physiology
Alzheimer Disease metabolism
Insulin pharmacology
Insulin Receptor Substrate Proteins metabolism
Insulin Resistance physiology
Nerve Growth Factor pharmacology
Septal Nuclei metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1559-1182
- Volume :
- 56
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular neurobiology
- Publication Type :
- Academic Journal
- Accession number :
- 29736736
- Full Text :
- https://doi.org/10.1007/s12035-018-1038-4