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-beta (A beta), 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 A beta-containing autophagic vacuoles. At the same time, plasma A beta 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 A beta. Neuronal IGF-1R, and possibly other cell size-controlling pathways are promising targets for AD treatment.