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APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology.
Tran, Kristine M; Kwang, Nellie; Gomez-Arboledas, Angela; Kawauchi, Shimako; Mar, Cassandra; Chao, Donna; Da Cunha, Celia; Wang, Shuling; Collins, Sherilyn; Walker, Amber; Shi, Kai-Xuan; Alcantara, Joshua A; Neumann, Jonathan; Tenner, Andrea J; LaFerla, Frank M; Hohsfield, Lindsay A; Swarup, Vivek; MacGregor, Grant R; Green, Kim N.
Afiliación
  • Tran KM; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
  • Kwang N; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
  • Gomez-Arboledas A; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
  • Kawauchi S; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
  • Mar C; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, CA 92697, USA.
  • Chao D; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
  • Da Cunha C; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
  • Wang S; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
  • Collins S; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, CA 92697, USA.
  • Walker A; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, CA 92697, USA.
  • Shi KX; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, CA 92697, USA.
  • Alcantara JA; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, CA 92697, USA.
  • Neumann J; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, CA 92697, USA.
  • Tenner AJ; Transgenic Mouse Facility, ULAR, Office of Research, University of California, Irvine, CA 92697, USA.
  • LaFerla FM; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
  • Hohsfield LA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
  • Swarup V; Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697, USA.
  • MacGregor GR; Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA.
  • Green KN; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
bioRxiv ; 2024 Jun 04.
Article en En | MEDLINE | ID: mdl-38895362
ABSTRACT

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 transcriptomics and 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.

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.
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Texto completo: 1 Banco de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos