ICA1L stabilizes LRP1 to mitigate Aβ pathology in Alzheimer’s disease

Abstract Background Genetic and proteomic studies have identified numerous candidate genes associated with Alzheimer’s disease (AD), yet the functional relevance of many remains unclear. Islet Cell Autoantigen 1 Like (ICA1L) has consistently emerged as a top-ranked locus in integrative genome-wide and proteome-wide association studies, but its mechanistic role in AD pathogenesis has not been defined. Methods ICA1L expression was examined in postmortem human AD brains and 5xFAD transgenic mice. Cognitive function and amyloid pathology were assessed using three independent ICA1L -deficient mouse models, including germline knockout, central nervous system-specific and excitatory neuron–specific knockouts. Hippocampal ICA1L overexpression was employed to evaluate the effects of enhanced ICA1L expression in vivo. ICA1L-interacting proteins were identified by immunoprecipitation followed by liquid chromatography–tandem mass spectrometry (LC-MS). Protein stability and degradation pathways were assessed using cycloheximide chase assays together with ubiquitination and inhibitor-based analyses. A structure-guided 30–amino acid ICA1L-derived peptide was engineered and evaluated for blood–brain barrier penetration and therapeutic efficacy in 5xFAD mice. Results ICA1L expression was significantly upregulated in the brains of AD patients and 5xFAD mice. Genetic ablation of ICA1L markedly exacerbated cognitive deficits and amyloid-β (Aβ) pathology, whereas hippocampal overexpression of ICA1L attenuated amyloid deposition and improved cognitive function. Interactomics analyses revealed that ICA1L physically interacts with low-density lipoprotein receptor-related protein 1 (LRP1). Loss of ICA1L accelerated LRP1 degradation via ubiquitin–proteasome pathways, resulting in increased BACE1 expression and enhanced Aβ production. Notably, a 30–amino acid synthetic peptide derived from ICA1L stabilized LRP1, alleviated Aβ pathology, and improved cognitive performance in 5xFAD mice. Conclusions These findings identify ICA1L as an endogenous neuroprotective regulator of AD pathology and uncover a previously unrecognized ICA1L–LRP1 axis that modulates Aβ homeostasis. Targeting ICA1L or its active peptide represents a promising therapeutic strategy for Alzheimer’s disease.