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Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype.
Fung, Susan; Smith, Carole L; Prater, Katherine E; Case, Amanda; Green, Kevin; Osnis, Leah; Winston, Chloe; Kinoshita, Yoshito; Sopher, Bryce; Morrison, Richard S; Garden, Gwenn A; Jayadev, Suman.
Afiliação
  • Fung S; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Smith CL; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Prater KE; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Case A; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Green K; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Osnis L; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Winston C; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Kinoshita Y; Department of Neurosurgery, University of Washington, Seattle, WA, USA.
  • Sopher B; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Morrison RS; Department of Neurosurgery, University of Washington, Seattle, WA, USA.
  • Garden GA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA.
  • Jayadev S; Department of Neurology, University of Washington, Seattle, WA, USA.
J Alzheimers Dis ; 77(2): 675-688, 2020.
Article em En | MEDLINE | ID: mdl-32741831
ABSTRACT

BACKGROUND:

Early-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and APP genes. Decades after their discovery, the mechanisms by which these genes cause Alzheimer's disease (AD) or promote AD progression are not fully understood. While it is established that presenilin (PS) enzymatic activity produces amyloid-ß (Aß), PSs also regulate numerous other cellular functions, some of which intersect with known pathogenic drivers of neurodegeneration. Accumulating evidence suggests that microglia, resident innate immune cells in the central nervous system, play a key role in AD neurodegeneration.

OBJECTIVE:

Previous work has identified a regulatory role for PS2 in microglia. We hypothesized that PSEN2 variants lead to dysregulated microglia, which could further contribute to disease acceleration. To mimic the genotype of EOFAD patients, we created a transgenic mouse expressing PSEN2 N141I on a mouse background expressing one wildtype PS2 and two PS1 alleles.

RESULTS:

Microglial expression of PSEN2 N141I resulted in impaired γ-secretase activity as well as exaggerated inflammatory cytokine release, NFκB activity, and Aß internalization. In vivo, PS2 N141I mice showed enhanced IL-6 and TREM2 expression in brain as well as reduced branch number and length, an indication of "activated" morphology, in the absence of inflammatory stimuli. LPS intraperitoneal injection resulted in higher inflammatory gene expression in PS2 N141I mouse brain relative to controls.

CONCLUSION:

Our findings demonstrate that PSEN2 N141I heterozygosity is associated with disrupted innate immune homeostasis, suggesting EOFAD variants may promote disease progression through non-neuronal cells beyond canonical dysregulated Aß production.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenótipo / Variação Genética / Microglia / Presenilina-2 / Doença de Alzheimer / Heterozigoto Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: J Alzheimers Dis Assunto da revista: GERIATRIA / NEUROLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenótipo / Variação Genética / Microglia / Presenilina-2 / Doença de Alzheimer / Heterozigoto Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: J Alzheimers Dis Assunto da revista: GERIATRIA / NEUROLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos