Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-β Clearance.

摘要: Alzheimer9s 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, pathway also implicated aging. Here we aimed protect the aging brain from devastating amyloid pathology by making specifically adult neurons resistant IGF signaling. To achieve that, knocked out neuronal IGF-1R during adulthood APP/PS1 mice. We found that mutants exhibited improved spatial memory reduced anxiety. Mutant brains displayed fewer plaques, less amyloid-β (Aβ), diminished neuroinflammation. Surprisingly, undergoing knock-out their apical soma developed leaner dendrites, indicative of remarkable structural plasticity entailing condensed forebrain neuroarchitecture. Neurons lacking showed accumulation Aβ-containing autophagic vacuoles. At same time, plasma Aβ levels were increased. Our data indicate ablation, via preserved compartment enhanced systemic elimination, offers lifelong protection clearing toxic Aβ. Neuronal IGF-1R, possibly other cell size-controlling pathways are promising targets for SIGNIFICANCE STATEMENT compelling evidence vivo progression significantly delayed when (IGF) signaling blocked neurons. show built novel mouse model, combining inducible neuron-specific with transgenics. Analysis experimental phenotype revealed abundant (Aβ) peptides, neuroinflammation inactivated together clearly behavioral performances. present first time has profound effects on proteostasis maintenance morphology . results model highly pertinent translational research resistance may represent pathophysiologically relevant mechanism preventing accumulation.