Multiple system atrophy and apolipoprotein E

Ogaki, Kotaro; Martens, Yuka A.; Heckman, Michael G.; Koga, Shunsuke; Labbé, Catherine; Lorenzo‐Betancor, Oswaldo; Wernick, Anna I.; Walton, Ronald L.; Soto, Alexandra I.; Vargas, Emily; Nielsen, Henrietta M.; Fujioka, Shinsuke; Kanekiyo, Takahisa; Uitti, Ryan J.; Gerpen, Jay A. van; Cheshire, William P.; Wszołek, Zbigniew K.; Low, Phillip A.; Singer, Wolfgang; Dickson, Dennis W.; Bu, Guojun; Ross, Owen A.

doi:10.1002/mds.27297

Cited by 18 publications

(13 citation statements)

References 17 publications

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“…The finding that a myelination-enriched gene module was positively associated with APOE2 genotype and negatively correlated with pSyn pathology is intriguing and may indicate that oligodendrocytes regulate either the pathologic aggregation of Syn or a compensatory response, in an APOE2-dependent manner. In the context of synucleinopathies, this is of particular interest given that MSA, an aggressive illness characterized by aggregates with high potency for pathologic seeding and spreading, is characterized by (54). The role of oligodendrocytes in the pathogenesis of MSA is not fully appreciated and is even less clear in PD and PD dementia but deserves more attention especially considering the strong associations we observed for APOE2 and pSyn pathology.…”

Section: Discussionmentioning

confidence: 93%

APOE genotype regulates pathology and disease progression in synucleinopathy

et al. 2020

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Apolipoprotein E (APOE) ε4 genotype is associated with increased risk of dementia in Parkinson’s disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. APOE ε4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether APOE genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on Apoe knockout (A53T/EKO) or human APOE knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes. In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice. In two separate cohorts of human patients with PD, APOE ε4/ε4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that APOE genotype directly regulates αSyn pathology independent of its established effects on Aβ and tau, corroborate the finding that APOE ε4 exacerbates pathology, and suggest that APOE ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.

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Section: Discussionmentioning

confidence: 93%

APOE genotype regulates pathology and disease progression in synucleinopathy

et al. 2020

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“…Our results confirmed previous studies of APOE in PD and MSA. [35][36][37][38][39][40] A genomewide association study (GWAS) performed on a small cohort of CBD also found no association of APOE with CBD. 41 Recently, a study of 134 CBD cases found no significant associations of ε2 or ε4 with disease risk.…”

Section: Discussionmentioning

confidence: 99%

Assessment of APOE in atypical parkinsonism syndromes

Sabir

Blauwendraat

Ahmed

et al. 2019

Neurobiology of Disease

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Atypical parkinsonism syndromes are a heterogeneous group of neurodegenerative disorders that include corticobasal degeneration (CBD), Lewy body dementia (LBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The APOE ε4 allele is a well-established risk factor for Alzheimer's disease; however, the role of APOE in atypical parkinsonism syndromes remains controversial. To examine the associations of APOE ε4 and ε2 alleles with risk of developing these syndromes, a total of 991 pathologically-confirmed atypical parkinsonism cases were genotyped using the Illumina NeuroChip array. We also performed genotyping and logistic regression analyses to examine APOE frequency and associated risk in patients with Alzheimer's disease (n=571) and Parkinson's disease (n=348). APOE genotypes were compared to those from neurologic ally healthy controls (n=591). We demonstrate that APOE ε4 and ε2 carriers have a significantly increased and decreased risk, respectively, of developing Alzheimer's disease (ε4:

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“…Although the association between APOE and PD has been disproved [ 267 – 269 ], evidence shows an increased risk of PDD in APOE*ε2 carriers [ 270 , 271 ]. Similar to PD, MSA appears to be also exempted from the impact of APOE [ 272 , 273 ].…”

Section: Main Textmentioning

confidence: 99%

APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

Shue

Zhao

et al. 2020

Mol Neurodegeneration

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119

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Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer’s disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition, APOE*ε2 has been identified as a longevity gene, suggesting a systemic effect of APOE*ε2 on the aging process. However, APOE*ε2 is not entirely benign; APOE*ε2 carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect of APOE*ε2 against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect of APOE2 to treat AD.

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Multiple system atrophy and apolipoprotein E

Cited by 18 publications

References 17 publications

APOE genotype regulates pathology and disease progression in synucleinopathy

APOE genotype regulates pathology and disease progression in synucleinopathy

Assessment of APOE in atypical parkinsonism syndromes

APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

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