Pan, Yining

Abstract INTRODUCTION Loss‐of‐function variants of the ABCA7 gene are associated with an increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown. METHODS Using neuron‐specific Abca7 KO mice (n Abca7 −/− ) with or without 5×FAD amyloid model background and post mortem AD brains, we investigated AD‐related phenotypes through comprehensive approaches including transcriptomics and lipidomics. RESULTS Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; n Abca7 −/− mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; n Abca7 −/− mice showed diminished mitochondria respiration and reduced synaptic protein levels, which is further supported by results from human AD brains. DISCUSSION Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology. Highlights Neuronal ABCA7 deficiency exacerbates Aβ pathology and neuronal damage in 5×FAD mice. Neuronal ABCA7 deficiency alters brain transcriptomes and lipidomes of 5×FAD mice. Neuronal ABCA7 deficiency disturbs mitochondria functions in synaptosomes from 5×FAD mice. Neuronal ABCA7 expression associates with genes and pathways related to mitochondrial homeostasis in AD brains.

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease and the most prevalent form of late‐life dementia. The ε2 allele of the APOE gene encoding apolipoprotein E (APOE2) is associated with lower susceptibility to AD among the three genotypes (ε2, ε3, ε4), while APOE4 is the strongest genetic risk factor for late‐onset AD. APOE plays a critical role in maintaining synaptic plasticity and neuronal function by controlling lipid homeostasis, with APOE2 having a superior function. Gene therapy that increases APOE2 levels in the brain has, therefore, emerged as a potential therapeutic strategy to treat AD.MethodWe conjugated PEGylated liposomes with transferrin and Penetratin, a cell‐penetrating peptide, sufficiently deliver chitosan‐APOE2 cDNA plasmid complex into amyloid model AppNL‐G‐F knockin mice at 12‐month‐old. Biochemical studies and brain transcriptome analysis were employed to investigate how brain‐targeting liposome‐based APOE2 gene delivery influences amyloid‐β (Aβ)‐related pathologies in AppNL‐G‐F knockin mice.ResultOne month after APOE2 gene therapy, there was a trend of reduced insoluble Aβ levels in the mouse cortices. Furthermore, in the AppNL‐G‐F knockin mice that received the APOE2 gene therapy, brain transcriptome analysis through RNA‐sequencing identified the upregulation of genes/pathways related to neuronal development. This was supported by increases of Dlg4 and Syp mRNAs coding synaptic proteins in the experimental group. On the other hand, we found that APOE2 gene delivery increased soluble Aβ levels, including oligomers, as well as exacerbated neurite dystrophy and decreased synaptophysin.ConclusionOur results suggest that brain‐targeting liposome‐based APOE2 gene therapy is potentially beneficial for synaptic formation at the transcriptional level. Forced APOE2 expressions, however, may exacerbate Aβ toxicity by increasing the dissociation of Aβ oligomers from aggregates in the presence of considerable amyloid burden.