👤 I Matias

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder thought to result from complex interactions between genetic and environmental risk factors. The APOE-ε4 allele is the strongest genetic contributor to late-onset AD, while a Western diet - high in saturated fats and refined sugars - is a major lifestyle-related risk factor associated with AD progression. However, how these two factors interact at an early stage of the disease remains unclear. In this study, we examined their combined impact on hippocampal synaptic transmission and plasticity in an AD mouse model and evaluated whether supplementation with d-serine, the key NMDAR co-agonist, could reverse the resulting deficits. To assess the combined effects of genetic and dietary risk factors on synaptic function, we crossed APP/PS1 mice with APOE-ε4 KI mice and generated four mouse lines: wild-type, APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4. Hippocampal synaptic transmission and plasticity, NMDAR function and d- and l-serine levels were evaluated using a combination of electrophysiological recordings, pharmacological interventions and capillary electrophoresis in brain slices, under either control or Western diet conditions. A significant impairment of both basal excitatory synaptic transmission and long-term potentiation (LTP) was detected in APP/PS1 mice by 9 months of age. These deficits were significantly more pronounced in APP/PS1/APOE-ε4 mice. Notably, Western diet accelerated these impairments, with significant deficits already present at 7 months in both APOE-ε4 and APP/PS1/APOE-ε4 mice. Mechanistically, these impairments were associated with reduced d-serine availability and NMDAR hypofunction at CA3-CA1 synapses. This study provides direct evidence of a specific and synergistic interaction between the APOE-ε4 genotype and Western diet in advancing and exacerbating hippocampal synaptic dysfunction in an AD mouse model. These findings highlight d-serine/NMDAR signaling as a key mechanistic pathway through which genetic and environmental risk factors converge in early AD, and underscore the potential of targeting astrocytic d-serine biosynthetic pathways as a promising therapeutic strategy for APOE-ε4 carriers at risk for late-onset AD. Not applicable. The online version contains supplementary material available at 10.1186/s13195-026-01992-y. Show less

Multiple genome-wide association studies (GWAS) have identified SNPs in the 8q24 locus near TRIB1 that are significantly associated with plasma lipids and other markers of cardiometabolic health, and prior studies have revealed the roles of hepatic and myeloid Trib1 in plasma lipid regulation and atherosclerosis. The same 8q24 SNPs are additionally associated with plasma adiponectin levels in humans, implicating TRIB1 in adipocyte biology. Here, we hypothesize that TRIB1 in adipose tissue regulates plasma adiponectin, lipids, and metabolic health. We investigate the metabolic phenotype of adipocyte-specific Trib1 knockout mice (Trib1_ASKO) fed on chow and high-fat diet (HFD). Through secretomics of adipose tissue explants and RNA-seq of adipocytes and livers from these mice, we further investigate the mechanism of TRIB1 in adipose tissue. Trib1_ASKO mice have an improved metabolic phenotype with increased plasma adiponectin levels, improved glucose tolerance, and decreased plasma lipids. Trib1_ASKO adipocytes have increased adiponectin production and secretion independent of the known TRIB1 function of regulating proteasomal degradation. RNA-seq analysis of adipocytes and livers from Trib1_ASKO mice indicates that alterations in adipocyte function underlie the observed plasma lipid changes. Adipose tissue explant secretomics further reveals that Trib1_ASKO adipose tissue has decreased ANGPTL4 production, and we demonstrate an accompanying increase in the lipoprotein lipase (LPL) activity that likely underlies the triglyceride phenotype. This study shows that adipocyte Trib1 regulates multiple aspects of metabolic health, confirming previously observed genetic associations in humans and shedding light on the further mechanisms by which TRIB1 regulates plasma lipids and metabolic health. Show less