Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-β Clearance.
Alzheimer's disease (AD) is a frequent and irreversible age-related neurodegeneration without efficient treatment. Experimental AD in mice responds positively to decreased insulin-like growth factor I (IGF-I) signaling, a pathway also implicated in aging. Here we aimed to protect the aging brain from devastating amyloid pathology by making specifically adult neurons resistant to IGF signaling. To achieve that, we knocked out neuronal IGF-1R during adulthood in APP/PS1 mice. We found that mutants exhibited improved spatial memory and reduced anxiety. Mutant brains displayed fewer amyloid plaques, less amyloid-β (Aβ), and diminished neuroinflammation. Surprisingly, adult neurons undergoing IGF-1R knock-out reduced their apical soma and developed leaner dendrites, indicative of remarkable structural plasticity entailing condensed forebrain neuroarchitecture. Neurons lacking IGF-1R in AD showed less accumulation of Aβ-containing autophagic vacuoles. At the same time, plasma Aβ levels were increased. Our data indicate that neuronal IGF-1R ablation, via preserved autophagic compartment and enhanced systemic elimination, offers lifelong protection from AD pathology by clearing toxic Aβ. Neuronal IGF-1R, and possibly other cell size-controlling pathways are promising targets for AD treatment.


CONCLUSIONS
We found compelling evidence in vivo that Alzheimer's disease (AD) progression is significantly delayed when insulin-like growth factor (IGF) signaling is blocked in adult neurons. To show that, we built a novel mouse model, combining inducible neuron-specific IGF-1R knock-out with AD transgenics. Analysis of the experimental AD phenotype revealed less abundant amyloid-β (Aβ) peptides, fewer plaques, and diminished neuroinflammation in mutants with inactivated IGF signaling, together with clearly preserved behavioral and memory performances. We present for the first time evidence that IGF signaling has profound effects on neuronal proteostasis and maintenance of cell morphology in vivo. Our results indicate in a model highly pertinent to translational research that neuronal IGF resistance may represent a pathophysiologically relevant mechanism of the brain for preventing Aβ accumulation.
Institut National de la Santé et de la Recherche Médicale, Centre de Recherche UMR938, Hôpital Saint-Antoine, 75012 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie, 75005 Paris, France, and.
Géraldine
http://orcid.org/0000-0003-2894-7282
G
Gontier
Institut National de la Santé et de la Recherche Médicale, Centre de Recherche UMR938, Hôpital Saint-Antoine, 75012 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie, 75005 Paris, France, and.
Caroline
C
George
Institut National de la Santé et de la Recherche Médicale, Centre de Recherche UMR938, Hôpital Saint-Antoine, 75012 Paris, France, Faculté de Médecine, Université Paris Descartes, 75006 Paris, France.
Zayna
http://orcid.org/0000-0001-9059-4866
Z
Chaker
Institut National de la Santé et de la Recherche Médicale, Centre de Recherche UMR938, Hôpital Saint-Antoine, 75012 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie, 75005 Paris, France, and martin.holzenberger@inserm.fr.
Martin
http://orcid.org/0000-0003-4869-725X
M
Holzenberger
Institut National de la Santé et de la Recherche Médicale, Centre de Recherche UMR938, Hôpital Saint-Antoine, 75012 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie, 75005 Paris, France, and.
Saba
S
Aïd
D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D048429:Cell Size; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D018782:Maze Learning; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000235:genetics; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
Alzheimer's disease; amyloid-β; conditional mutagenesis; insulin-like growth factor; mouse model; neuron