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bioRxiv · 10.1101/2025.11.05.686857

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

Soto-Faguas, C. M.·O'Niel, A.·Mueller, P. A.·Sanchez-Molina, P.·Woltjer, R. L.·Raber, J.·Unni, V. K.
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Abstract

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

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Soto-Faguas, C. M., O'Niel, A., Mueller, P. A., Sanchez-Molina, P., Woltjer, R. L., Raber, J., Unni, V. K.. 2025-11-07. The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologies. https://doi.org/10.1101/2025.11.05.686857

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