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Background Apolipoprotein E ε4 ( APOE4 ) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). A recent case report identified a rare variant in APOE, APOE3 -R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer’s Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects. Methods We introduced the R136S variant into mouse Apoe ( ApoeCh ) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain’s response to plaques and tau. Results In 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh . We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh . Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice. Conclusions These findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming. Graphical Abstract

The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer's Disease (AD). Unfortunately, many current Trem2 mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2 (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products. Trem2 mice were treated with the demyelinating agent cuprizone, or crossed with the 5xFAD mouse model of amyloidosis, to explore the impact of the TREM2 R47H variant on inflammatory responses to demyelination, plaque development, and the brain's response to plaques. Trem2 mice display an appropriate inflammatory response to cuprizone challenge, and do not recapitulate the null allele in terms of impeded inflammatory responses to demyelination. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in Trem2 mice in response to development of AD-like pathology. At an early (4-month-old) disease stage, hemizygous 5xFAD/homozygous Trem2 (5xFAD/Trem2 ) mice have reduced size and number of microglia that display impaired interaction with plaques compared to microglia in age-matched 5xFAD hemizygous controls. This is associated with a suppressed inflammatory response but increased dystrophic neurites and axonal damage as measured by plasma neurofilament light chain (NfL) level. Homozygosity for Trem2 suppressed LTP deficits and loss of presynaptic puncta caused by the 5xFAD transgene array in 4-month-old mice. At a more advanced (12-month-old) disease stage 5xFAD/Trem2 mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Twelve-month old Trem2 mice also display LTP deficits and postsynaptic loss. The Trem2 mouse is a valuable model that can be used to investigate age-dependent effects of the AD-risk R47H mutation on TREM2 and microglial function including its effects on plaque development, microglial-plaque interaction, production of a unique interferon signature and associated tissue damage.

Background In several large genome‐wide association studies (GWAS), genetic polymorphisms of Abi3 have been identified as a risk factor for late‐onset Alzheimer’s Disease (LOAD). ABI3 along with ABI1 and ABI2, regulate the formation of the WAVE complex which in turn, regulates actin dynamics. ABI3 is highly expressed in microglia in the brain, however, the function of ABI3 in microglia is relatively unknown. In recent studies knock‐out of ABI3 has been shown to exacerbate amyloid beta (Aβ) pathology and associated inflammation. To date, there have been no studies on variant specific effects on amyloid beta pathology. Methods To study the effects of ABI3 on the development of Alzheimer’s disease (AD) relevant pathologies we introduced an equivalent coding sequence change that has been identified as a risk variant for LOAD (S212F) into the C57BL/6 mouse genome using CRISPR/Cas9 (S209F). We set out to characterize the Abi3S209F variant and investigate its impact on AD pathology when crossed with 5xFAD transgenic mice, generating four distinct groups: WT, Abi3S209F homozygous, 5xFAD, and 5xFAD/Abi3S209F homozygous. Characterization was performed using histological staining and biochemical approaches at 4‐, 12‐ and 18‐months of age. Results 5xFAD/Abi3S209F mice displayed an age‐related decrease in dense core‐Aβ plaque burden, characterized by reduced Thioflavin‐S staining, accompanied by changes in fibrillar Aβ (OC) staining, in confocal images of both subiculum and visual cortical regions of 5xFAD/Abi3S209F mice compared to 5xFAD mice. Broadly, microglial numbers mimic plaque load, however by 18‐months of age 5xFAD/Abi3S209F mice display dramatic reductions in IBA1+ microglia number – to levels comparable to WT/Abi3S209F homozygous mice, suggesting a general loss of plaque associated microglia. By 12 months of age, Abi3S209F homozygous and 5xFAD/ Abi3S209F mice displayed increased synaptic density, independent of pathology in visual cortex, subiculum and CA1 regions. Conclusions Together, these results characterize the effects of the Abi3S209F missense mutation on 5xFAD‐mediated pathology, specifically in Aβ plaque development, glial morphology, and synapses. Our data suggests that this mutation may affect microglia dynamics in an age‐dependent manner and may result in dysfunctional microglia at later stages of disease.

Background The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer’s Disease (AD). Unfortunately, many current Trem2 R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2 R47H NSS ( N ormal S plice S ite) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products. Methods Trem2 R47H NSS mice were treated with the demyelinating agent cuprizone, or crossed with the 5xFAD mouse model of amyloidosis, to explore the impact of the TREM2 R47H variant on inflammatory responses to demyelination, plaque development, and the brain’s response to plaques. Results Trem2 R47H NSS mice display an appropriate inflammatory response to cuprizone challenge, and do not recapitulate the null allele in terms of impeded inflammatory responses to demyelination. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in Trem2 R47H NSS mice in response to development of AD-like pathology. At an early (4-month-old) disease stage, hemizygous 5xFAD/homozygous Trem2 R47H NSS (5xFAD/ Trem2 R47H NSS ) mice have reduced size and number of microglia that display impaired interaction with plaques compared to microglia in age-matched 5xFAD hemizygous controls. This is associated with a suppressed inflammatory response but increased dystrophic neurites and axonal damage as measured by plasma neurofilament light chain (NfL) level. Homozygosity for Trem2 R47H NSS suppressed LTP deficits and loss of presynaptic puncta caused by the 5xFAD transgene array in 4-month-old mice. At a more advanced (12-month-old) disease stage 5xFAD/ Trem2 R47H NSS mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Twelve-month old Trem2 R47H NSS mice also display LTP deficits and postsynaptic loss. Conclusions The Trem2 R47H NSS mouse is a valuable model that can be used to investigate age-dependent effects of the AD-risk R47H mutation on TREM2 and microglial function including its effects on plaque development, microglial-plaque interaction, production of a unique interferon signature and associated tissue damage.

In several large genome-wide association studies (GWAS), genetic polymorphisms of Abi3 have been identified as a risk factor for late-onset Alzheimer's Disease (LOAD). ABI3 along with ABI1 and ABI2, regulate the formation of the WAVE complex which in turn, regulates actin dynamics. ABI3 is highly expressed in microglia in the brain, however, the function of ABI3 in microglia is relatively unknown. In recent studies knock-out of ABI3 has been shown to exacerbate amyloid beta (Aβ) pathology and associated inflammation. To date, there have been no studies on variant specific effects on amyloid beta pathology. To study the effects of ABI3 on the development of Alzheimer's disease (AD) relevant pathologies we introduced an equivalent coding sequence change that has been identified as a risk variant for LOAD (S212F) into the C57BL/6 mouse genome using CRISPR/Cas9 (S209F). We set out to characterize the Abi3 variant and investigate its impact on AD pathology when crossed with 5xFAD transgenic mice, generating four distinct groups: WT, Abi3 homozygous, 5xFAD, and 5xFAD/Abi3 homozygous. Characterization was performed using histological staining and biochemical approaches at 4-, 12- and 18-months of age. 5xFAD/Abi3 mice displayed an age-related decrease in dense core-Aβ plaque burden, characterized by reduced Thioflavin-S staining, accompanied by changes in fibrillar Aβ (OC) staining, in confocal images of both subiculum and visual cortical regions of 5xFAD/Abi3 mice compared to 5xFAD mice. Broadly, microglial numbers mimic plaque load, however by 18-months of age 5xFAD/Abi3 mice display dramatic reductions in IBA1+ microglia number - to levels comparable to WT/Abi3 homozygous mice, suggesting a general loss of plaque associated microglia. By 12 months of age, Abi3 homozygous and 5xFAD/ Abi3 mice displayed increased synaptic density, independent of pathology in visual cortex, subiculum and CA1 regions. Together, these results characterize the effects of the Abi3 missense mutation on 5xFAD-mediated pathology, specifically in Aβ plaque development, glial morphology, and synapses. Our data suggests that this mutation may affect microglia dynamics in an age-dependent manner and may result in dysfunctional microglia at later stages of disease.

INTRODUCTION The BIN1 coding variant rs138047593 (K358R) is linked to Late‐Onset Alzheimer's Disease (LOAD) via targeted exome sequencing. METHODS To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock‐in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology. RESULTS The presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild‐type and 5xFAD backgrounds homozygous for the BIN1K358R variant. DISCUSSION The BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities. Highlights BIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12‐month‐old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

BACKGROUND Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). METHODS CRISPR‐Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed. RESULTS Abca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S‐positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ‐associated inflammation, gliosis, and neuronal damage. DISCUSSION Overall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease‐related pathology. Highlights ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta‐associated damage in 5xFAD mice.

Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). CRISPR-Cas9 was used to generate an Abca7 variant in mice, modeling the homologous human ABCA7 variant, and extensive characterization was performed. Abca7 microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7 mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7 mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ-associated inflammation, gliosis, and neuronal damage. Overall, homozygosity for the Abca7 variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology. ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.