👤 Gabriel Aumont-Rodrigue

Apolipoprotein B (APOB), a structural component of low-density lipoproteins (LDL), has historically been associated with peripheral lipid transport and cardiovascular disease. Recent studies have revealed a link between APOB and Alzheimer's disease (AD), with increased cerebrospinal fluid (CSF) APOB levels correlating with tau pathology. Although APOB is known to be locally expressed in the brain, albeit at very low levels, its function in the central nervous system and contribution to neurodegenerative processes remains poorly understood. To investigate the effects of chronic APOB overexpression on brain molecular homeostasis, we used a transgenic mouse model expressing human APOB-100 and integrated findings with human cohort data to assess its functional relevance to AD pathology. Human APOB transgenic (hAPOB) and wild-type mice were aged to 6 and 12 months. Frontal cortices were analyzed using RNA sequencing and mass spectrometry-based proteomics. Differentially expressed genes and proteins were analyzed via pathway enrichment and cell type deconvolution. Findings were contrasted to post-mortem proteomic alterations observed in brain tissue (ROSMAP) and in the CSF (ADNI). hAPOB overexpression in mice induced a robust and persistent upregulation of innate immune genes, particularly those associated with type I interferon responses (Irf7, Ifit1, Oas2), in both young and old transgenic mice. Reduced microglial and endothelial cell signatures were observed through cell type deconvolution, which suggests immune activation without proliferation and possible blood-brain barrier damage. Proteomic analyses showed differentially expressed proteins associated with oxidative stress and dendritic remodeling. Proteins dysregulated in mice-such as CTSD, CRK, and SULT4A1-also showed altered expression in AD human brain and CSF. Remarkably, these proteins are dysregulated in the opposite direction in humans than in mice, unveiling a complex downstream regulation of APOB overexpression. Chronic hAPOB overexpression drives sustained neuroinflammatory and oxidative responses, potentially mimicking viral-like immune activation in the brain. The proteins dysregulated in hAPOB transgenic mice brains were also dysregulated in humans on opposite side of the APOB level spectrum. Nevertheless, this result shows a consistency across species on hAPOB-driven downstream effects. Some of these proteins were also shown to associate with key features of AD pathology, namely Aβ, Tau and pTau. Our findings support a novel role for APOB in modulating brain immune homeostasis and neurodegenerative processes, offering a mechanistic link between vascular risk and Alzheimer's disease. Show less

Apolipoprotein B (APOB), a receptor-binding protein present in cholesterol-rich lipoproteins, has been implicated in Alzheimer's disease (AD). High levels of APOB-containing low-density lipoproteins (LDL) are linked to the pathogenesis of both early-onset familial and late-onset sporadic AD. Rare coding mutations in the APOB gene are associated with familial AD, suggesting a role for APOB-bound lipoproteins in the central nervous system. This research explores APOB gene regulation across the AD spectrum using four cohorts: BRAINEAC (elderly control brains), DBCBB (controls, AD brains), ROSMAP (controls, MCI, AD brains), and ADNI (control, MCI, AD clinical subjects). APOB protein levels, measured via mass spectrometry and ELISA, positively correlated with AD pathology indices and cognition, while APOB mRNA levels showed negative correlations. Brain APOB protein levels are also correlated with cortical Aβ levels. A common coding variant in the APOB gene locus affected its expression but didn't impact AD risk or brain cholesterol concentrations, except for 24-S-hydroxycholesterol. Polymorphisms in the CYP27A1 gene, notably rs4674344, were associated with APOB protein levels. A negative correlation was observed between brain APOB gene expression and AD biomarker levels. CSF APOB correlated with Tau pathology in presymptomatic subjects, while cortical APOB was strongly associated with cortical Aβ deposition in late-stage AD. The study discusses the potential link between blood-brain barrier dysfunction and AD symptoms in relation to APOB neurobiology. Overall, APOB's involvement in lipoprotein metabolism appears to influence AD pathology across different stages of the disease. Show less