The Alzheimer's disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons

Abstract

Seminal studies using post-mortem brains of patients with Alzheimer's disease evidenced aberrant insulin-like growth factor 1 receptor (IGF1R) signalling. Addressing causality, work in animal models recently demonstrated that long-term suppression of IGF1R signalling alleviates Alzheimer's disease progression and promotes neuroprotection. However, the underlying mechanisms remain largely elusive. Here, we showed that genetically ablating IGF1R in neurons of the ageing brain efficiently protects from neuroinflammation, anxiety and memory impairments induced by intracerebroventricular injection of amyloid-β oligomers. In our mutant mice, the suppression of IGF1R signalling also invariably led to small neuronal soma size, indicative of profound changes in cellular homeodynamics. To gain insight into transcriptional signatures leading to Alzheimer's disease-relevant neuronal defence, we performed genome-wide microarray analysis on laser-dissected hippocampal CA1 after neuronal IGF1R knockout, in the presence or absence of APP/PS1 transgenes. Functional analysis comparing neurons in early-stage Alzheimer's disease with IGF1R knockout neurons revealed strongly convergent transcriptomic signatures, notably involving neurite growth, cytoskeleton organization, cellular stress response and neurotransmission. Moreover, in Alzheimer's disease neurons, a high proportion of genes responding to Alzheimer's disease showed a reversed differential expression when IGF1R was deleted. One of the genes consistently highlighted in genome-wide comparison was the neurofilament medium polypeptide Nefm. We found that NEFM accumulated in hippocampus in the presence of amyloid pathology, and decreased to control levels under IGF1R deletion, suggesting that reorganized cytoskeleton likely plays a role in neuroprotection. These findings demonstrated that significant resistance of the brain to amyloid-β can be achieved lifelong by suppressing neuronal IGF1R and identified IGF-dependent molecular pathways that coordinate an intrinsic program for neuroprotection against proteotoxicity. Our data also indicate that neuronal defences against Alzheimer's disease rely on an endogenous gene expression profile similar to the neuroprotective response activated by genetic disruption of IGF1R signalling. This study highlights neuronal IGF1R signalling as a relevant target for developing Alzheimer's disease prevention strategies.