O'Niel, A. | bioRxiv Science

bioRxiv2025

The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologies

Apolipoprotein E (APOE) genotype is well known to influence both amyloid-{beta} (A{beta}) and tau pathologies and risk for Alzheimers disease (AD), but it also affects -synuclein (-syn) levels, Lewy pathology and risk of dementia in Parkinsons disease (PD) and dementia with Lewy bodies (DLB). The APOE-R136S (Christchurch, CC) point mutation has been shown to protect against AD pathology and dementia, however, the molecular mechanisms underlying this protection and its effects on -syn pathology are not well understood. Using CRISPR/Cas9 technology, we created a CC arginine-to-serine point mutation at the conserved location in mouse APOE (R128S) to understand its effects on A{beta}, tau and -syn pathologies. We crossed these APOE CC mice to 5xFAD, PS19 and A53T-Syn-GFP (A53T) mice. Using these various double mutant mice, we tested the effect of mouse APOE CC on different proteinopathies, including A{beta}, tau, A{beta}-induced tau after paired helical filament (PHF)-tau intracortical injections, and -syn after preformed fibril (PFF) intracortical and intramuscular injections. We used immunohistochemical, biochemical and behavioral measures to test for protective effects of APOE CC on these different proteinopathies. Heterozygous (Het) and homozygous (Hom) APOE CC mice showed increased plasma cholesterol and triglyceride levels, as seen in humans, but no differences in body or brain weight, or life expectancy. APOE CC decreased A{beta}-induced tau pathologies in PHF-tau injected 5xFAD;Hom mice but did not change A{beta}-plaque pathology in 5xFAD mice or tau pathology in PS19 mice. Although A{beta} levels, tau levels and mouse sex correlated strongly with the behavioral performance, we only detected subtle effects of APOE CC on anxiety-like behaviors in crosses with 5xFAD, PS19 and PHF-tau injected 5xFAD mice. Interestingly, Het and Hom APOE CC mice both showed reduced formation and spread of Lewy pathology in brain after intracortical -syn PFF injection and reduced formation in spinal cord after -syn PFF injection into the hindlimb gastrocnemius muscle in A53T mice. Our study emphasizes the protective effects of the APOE CC variant against different proteinopathies important for dementia and movement disorders, including A{beta} plaque, tau and -syn, and suggests that targeting APOE CC could provide new therapeutic strategies for AD, DLB and PD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/686857v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1104377org.highwire.dtl.DTLVardef@bd6c70org.highwire.dtl.DTLVardef@1a4e44org.highwire.dtl.DTLVardef@1087d7f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Epigenetic and Transcriptomic Alterations Precede Amyloidosis in the Hippocampus of the Alzheimer's Disease AppNL-G-F Knock in Mouse Model

Detecting and understanding the early stages of Alzheimers disease (AD) is essential for uncovering initial mechanisms of neuropathology and devising effective interventions. In this study, we leveraged the humanized AppNL-G-F mouse which exhibits early-onset amyloid pathology with a predictable timeline, to investigate molecular changes in the hippocampus and blood before the onset of severe neuropathology and independent of aging. Employing a multi-omics approach, we identified alterations in chromatin accessibility, gene expression, and DNA methylation associated with early amyloidosis. Chromatin accessibility changes were prominent in excitatory neurons during early pathology, with a later shift to inhibitory neurons, potentially reflecting compensatory mechanisms to mitigate excitatory neuron dysregulation. Despite broadly comparable hippocampal cell composition, transcriptomic comparisons between wild-type and AppNL-G-F mice revealed major gene expression differences, particularly in pathways related to mitochondrial function and protein biosynthesis, preceding severe amyloid plaque deposition. In later stages, upregulation of immune and neuroinflammatory pathways was observed, aligning with established neuroinflammatory processes in AD. Additionally, we identified extensive DNA methylation differences in both the blood and hippocampus of AppNL-G-Fmice during early and late stages of pathology. Many differentially methylated regions in the blood, even at early pathology stages, were associated with cis-regulatory elements in the brain and were located near differentially expressed genes in the hippocampus. These regions were enriched in pathways associated with brain function, including neuron development and synaptic processes, highlighting a connection between blood methylation patterns and brain activity. This finding suggests the potential use of blood DNA methylation as a biomarker for the early detection of amyloidosis. Notably, we identified five candidate biomarker genes, including Rbfox1 and Camta1, with epigenetic dysregulation detectable in both the brain and blood prior to severe amyloid accumulation. Our study, leveraging a unique AD mouse model and a multi-omics approach, highlights epigenetic signatures of AD before the onset of clinical symptoms, providing a foundation for future research into early diagnosis and therapeutic strategies, as well as potential blood biomarkers.

molecular biology↗