Biology subjects

Nazarenkov, N.

Publications and source records attributed to Nazarenkov, N..

3 recordsLinked to original sources

bioRxiv2026

Excessive cholesterol accumulation in microglia increases neuronal synaptic vulnerability to amyloid-beta

Cholesterol efflux is an important determinant of cellular lipid homeostasis. However, how microglial excessive cholesterol accumulation affects neuronal synaptic integrity remains poorly understood, particularly in the context of Alzheimer's disease. Here, we utilized a conditional knockout mouse model targeting the cholesterol transporters ABCA1 and ABCG1 in microglia. The microglia-specific ABCA1/ABCG1 deficiency triggered marked cholesterol accumulation, microglial hypertrophy, downregulation of the homeostatic marker P2ry12, and upregulation of the reactivity-associated marker CD11b, indicating shift toward a reactive phenotype. This phenotype was accompanied by increased reactive oxygen species, consistent with enhanced oxidative stress in ABCA1/ABCG1-deficient microglia compared with control. Using organotypic hippocampal slice cultures, we investigated the downstream neuronal outcomes of microglial ABCA1/ABCG1 deficiency. Under basal conditions, microglial ABCA1/ABCG1 knockdown did not significantly alter dendritic spine density in CA1 pyramidal neurons. However, upon exposure to amyloid-beta (A{beta}) stress, microglial ABCA1/ABCG1 deficiency markedly exacerbated dendritic spine loss in CA1 pyramidal neurons. Taken together, our findings highlight an important role for ABCA1/ABCG1-dependent cholesterol efflux in maintaining microglial homeostasis and limiting neuronal synaptic vulnerability to A{beta}-associated stress. These results support further investigation of microglial cholesterol transport as a potential target for preserving synaptic resilience in Alzheimer's disease.

neuroscience↗

bioRxiv2025

Progressive Loss of Astrocytic AIBP Expression during Alzheimer's Disease Pathology

Astrocytes and microglia play crucial roles in mediating neuroinflammation during Alzheimers disease (AD) progression. ApoA-I binding protein (APOA1BP, also known as AIBP/NAXE) attenuates neuroinflammation by blocking amyloid {beta}-induced TLR4 inflammaraft formation and oxidative stress. Apoa1bp knockout in APP/PS1 mice exacerbates microgliosis, increases amyloid plaque burden, neuronal cell loss, and reduces survival at 6 months. Although APOA1BP mRNA is ubiquitously expressed in humans, its cell-type-specific distribution in the brain remains unclear. To examine AIBP protein expression in the human brain, we performed immunohistochemistry on hippocampal sections from postmortem brain specimens from subjects aged 75-96 of both sexes. Using GFAP and IBA1 to label astrocytes and microglia, respectively, we found that AIBP protein was highly expressed in astrocytes, but not in microglia. Stratification of subjects by Braak stage (I-II, III-IV, V-VI) revealed a progressive decline in astrocytic AIBP expression with advancing AD pathology. Meta-analysis of RNA-seq profiling indicated enriched Apoa1bp expression in adult mouse astrocytes. Systemic Apoa1bp knockout in the APP/PS1 mouse exacerbated astrogliosis. These findings demonstrate that AIBP is predominantly expressed in astrocytes and its expression declines with AD progression, suggesting a potential role for AIBP in astrocyte-mediated neuroprotection and AD pathogenesis.

neuroscience↗

bioRxiv2025

Increased atherosclerosis and expression of inflammarafts in macrophage foam cells in AIBP-deficient mice

Atherosclerotic lesions comprise different populations of macrophages, including lipid-laden macrophage foam cells and non-foamy, inflammatory macrophages, which play distinct roles in disease progression. Non-foamy macrophages express higher levels of inflammarafts - enlarged, cholesterol-rich lipid rafts hosting assemblies of inflammatory receptors - compared to foam cells in atherosclerotic lesions of Ldlr-/-mice. Apolipoprotein A-I binding protein (AIBP) has been shown to control lipid raft dynamics. This study investigated the effect of systemic AIBP deficiency on inflammaraft expression in foam cells and non-foamy macrophages in atherosclerotic lesions of hypercholesterolemic mice. A larger number of foam cells, with increased neutral lipid accumulation, populated atherosclerotic lesions in Apoa1bp-/-Ldlr-/-mice compared to Ldlr-/- mice. Importantly, AIBP-deficient foam cells expressed higher levels of TLR4 dimers and lipid rafts (markers of inflammarafts) than control mice, accompanied by larger atherosclerotic lesions and larger necrotic cores compared to Ldlr-/-mice. In a model of foam cells, Apoa1bp-/- bone marrow-derived macrophages incubated with oxidized LDL had increased expression of inflammation- and atherosclerosis-related genes. These results indicate that AIBP deficiency is associated with a proinflammatory transition of foam cells in which increased lipid accumulation is paradoxically associated with an increased expression of inflammarafts and correlates with the development of advanced atherosclerotic plaques.

immunology↗