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

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.