APOE genotype regulates pathology and disease progression in synucleinopathy

Abstract

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.

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

“…However, none of these reports assessed the exact nature of the accumulating ␣Syn. A qualitative western blot analysis using Syn1 and MJFR-13 antibodies detecting total ␣Syn and pS129-␣Syn respectively revealed ∼23 kDa and ∼30 kDa bands, in addition to monomeric ∼14 kDa ␣Syn, in the SDS-soluble fraction of symptomatic G2.3 TgA53T mice which the authors interpreted as o-␣Syn oligomers [145]. Several points are problematic with this analysis: (i) there are no quantitative measurements provided; (ii) these additional bands are detected in symptomatic TgA53T/E4, TgA53T/E3 and TgA53T lacking murine APOE (TgA53T/EKO) with no apparent difference across APOE genotype; (iii) the molecular weights (∼23 kDa and ∼30 kDa) are inconsistent with those previously reported for o-␣Syn by electrophoretic separation as discussed above in this section.…”

“…Lastly, two very recent studies from the Holtzman and Bu groups investigated whether APOE 4 genotype, a major risk factor for neurodegenerative diseases, affected ␣Syn pathology in mice and subjects with PD [144,145]. While both studies relied on APOE knock-in (E2/E3/E4) backgrounds to compare the impact of APOE 2/3/4 alleles in mouse models of synucleinopathy, Davis and colleagues used G2.3 TgA53T mice [145]; Zhao and coworkers opted for an AAV-mediated overexpression of human ␣Syn WT , which does not cause amyloid inclusions as defined by a lack of Thioflavin-S positivity [144,146]. In both experimental settings, E4 exacerbated ␣Syn pathology, including pathological conformational changes detected by the antibody 5G4 and pS129-␣Syn accumulation, and worsened motor deficits.…”

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

“…Lewy body spectrum diseases • APOE polymorphisms contribute to sex-specific risk for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) ( Table 1 ). • The APOE ε4 allele worsens α-synuclein pathology ( Davis et al, 2020 ; Dickson et al, 2018 ; Zhao et al, 2020a ) and cognitive function in PD ( Mata et al, 2014 ). • Dopamine transporter activity in the nigrostriatal dopaminergic system may underlie sex-specific vulnerability for developing PD ( Gillies and McArthur, 2010 ), as males exhibit less efficient uptake and vesicular packaging of dopamine than females ( Bhatt and Dluzen, 2005 ), possibly due to male-specific gene expression ( Cantuti-Castelvetri et al, 2007 ) or renin-angiotensin system activity in the substantia nigra ( Rodriguez-Perez et al, 2010 ).…”

Apolipoprotein E4, Amyloid, and Cognition in Alzheimer’s and Lewy Body Disease

“…The effect of LBD on occipital β-amyloid deposition could be attributed to the signi cant interaction between LBD and APOE4. Since APOE4 is also involved in the spread of α-synuclein or LB pathology [6,18,43,44], as well as the co-existence of α-synuclein and βamyloid pathologies [11,45], APOE4 could play a pivotal role in the interaction between α-synuclein and β-amyloid [19]. In our study, the interaction of APOE4 with LBD was associated with poorer CDR-SOB scores.…”