APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology

Jin, Yunjung; Li, Fuyao; Sonoustoun, Berkiye; Kondru, Naveen; Martens, Yuka A.; Qiao, Wenhui; Heckman, Michael G.; Ikezu, Tadafumi C.; Li, Zonghua; Burgess, Jeremy D.; Amerna, Danilyn; O’Leary, Justin; DeTure, Michael; Zhao, Jing; McLean, Pamela J.; Dickson, Dennis W.; Ross, Owen A.; Bu, Guojun; Zhao, Na

doi:10.1007/s00401-022-02421-8

Cited by 33 publications

(34 citation statements)

References 71 publications

(85 reference statements)

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“…APOE4 has also been implicated in the progression of cognitive impairment or motor dysfunction within PD [54][55][56][57][58][59][60][61]. Recently, we reported that the presence of APOE4 gene allele exacerbates α-Syn seeding in a large AD cohort and a small cohort of LBD cases [62]. These findings indicate that APOE4 may potentially accelerate α-Syn aggregation and spreading during the disease [63].…”

Section: Discussionmentioning

confidence: 74%

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LRP1 is a neuronal receptor for α-synuclein uptake and spread

Chen

Martens

Meneses

et al. 2022

Mol Neurodegeneration

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Background The aggregation and spread of α-synuclein (α-Syn) protein and related neuronal toxicity are the key pathological features of Parkinson’s disease (PD) and Lewy body dementia (LBD). Studies have shown that pathological species of α-Syn and tau can spread in a prion-like manner between neurons, although these two proteins have distinct pathological roles and contribute to different neurodegenerative diseases. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP1) regulates the spread of tau proteins; however, the molecular regulatory mechanisms of α-Syn uptake and spread, and whether it is also regulated by LRP1, remain poorly understood. Methods We established LRP1 knockout (LRP1-KO) human induced pluripotent stem cells (iPSCs) isogenic lines using a CRISPR/Cas9 strategy and generated iPSC-derived neurons (iPSNs) to test the role of LRP1 in α-Syn uptake. We treated the iPSNs with fluorescently labeled α-Syn protein and measured the internalization of α-Syn using flow cytometry. Three forms of α-Syn species were tested: monomers, oligomers, and pre-formed fibrils (PFFs). To examine whether the lysine residues of α-Syn are involved in LRP1-mediated uptake, we capped the amines of lysines on α-Syn with sulfo-NHS acetate and then measured the internalization. We also tested whether the N-terminus of α-Syn is critical for LRP1-mediated internalization. Lastly, we investigated the role of Lrp1 in regulating α-Syn spread with a neuronal Lrp1 conditional knockout (Lrp1-nKO) mouse model. We generated adeno-associated viruses (AAVs) that allowed for distinguishing the α-Syn expression versus spread and injected them into the hippocampus of six-month-old Lrp1-nKO mice and the littermate wild type (WT) controls. The spread of α-Syn was evaluated three months after the injection. Results We found that the uptake of both monomeric and oligomeric α-Syn was significantly reduced in iPSNs with LRP1-KO compared with the WT controls. The uptake of α-Syn PFFs was also inhibited in LRP1-KO iPSNs, albeit to a much lesser extent compared to α-Syn monomers and oligomers. The blocking of lysine residues on α-Syn effectively decreased the uptake of α-Syn in iPSNs and the N-terminus of α-Syn was critical for LRP1-mediated α-Syn uptake. Finally, in the Lrp1-nKO mice, the spread of α-Syn was significantly reduced compared with the WT littermates. Conclusions We identified LRP1 as a key regulator of α-Syn neuronal uptake, as well as an important mediator of α-Syn spread in the brain. This study provides new knowledge on the physiological and pathological role of LRP1 in α-Syn trafficking and pathology, offering insight for the treatment of synucleinopathies.

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Section: Discussionmentioning

confidence: 74%

“…Human iPSCs were differentiated into neurons as previously described [31,32]. Briefly, iPSCs were maintained in Matrigel (Corning, cat# 354277)-coated plates using mTeSR ™ 1 medium (Stemcell Technologies, cat# 85850).…”

Section: Differentiation Of Human Ipscs Into Neuronsmentioning

confidence: 99%

LRP1 is a neuronal receptor for α-synuclein uptake and spread

Chen

Martens

Meneses

et al. 2022

Mol Neurodegeneration

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“…LB pathology is an additional neuropathological lesion found in approximately half of autopsy-confirmed AD patients [ 14 ]. Research has shown that APOE4 exacerbates the activity and neurotoxicity of α-synuclein, the primary constituent of LB pathology [ 15 ]. The objective of this study was to refine our previous findings by additionally adjusting for covariates (age, education, MMSE scores) and comparing neuropsychiatric symptom profiles between at-risk and not-at-risk females.…”

Section: Introductionmentioning

confidence: 99%

Determining Whether Sex and Zygosity Modulates the Association between APOE4 and Psychosis in a Neuropathologically-Confirmed Alzheimer’s Disease Cohort

et al. 2022

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Background: The APOE4 allele is a genetic risk factor for developing late-onset Alzheimer’s disease (AD). Previous work by our group revealed that female APOE4 homozygotes with Lewy body (LB) pathology were more likely to experience psychosis compared to female APOE4 non-carriers, whereas in males there was no APOE4 dose-dependent significant effect. The objective of this study was to refine our previous findings by adjusting for covariates and determining the probability of an APOE4 sex-mediated effect on psychosis. Methods: Neuropathologically confirmed AD patients with LB pathology (n = 491) and without LB pathology (n = 716) were extracted from the National Alzheimer’s Coordinating Center (NACC). Patients were classified as psychotic if they scored positively for delusions and/or hallucinations on the Neuropsychiatric Inventory. Analysis consisted of a preliminary unadjusted binary logistic regression and a Generalized Additive binary logistic regression Model (GAM) to predict the relationship between APOE4 status and sex on the presence of psychosis in both cohorts, adjusting for age, education and MMSE. Results: In the cohort with LB pathology, female APOE4 homozygotes were significantly more likely to experience psychosis compared to female APOE4 non-carriers (OR = 4.15, 95%CI [1.21, 14.2], p = 0.023). Female heterozygotes were also more likely to experience psychosis compared to female APOE4 non-carriers, but to a lesser extent (OR = 2.37, 95%CI [1.01, 5.59], p = 0.048). There was no significant difference in males with LB pathology or in any sex in the cohort without LB pathology. Conclusions: Sex and zygosity influence the effect of APOE4 on psychosis in neuropathologically confirmed AD patients, with the effect being limited to females with LB pathology.

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“…Recently, Bassi et al demonstrated that amyloid-β (Aβ) deposits dramatically accelerate α-Syn pathogenesis and spread throughout the brain after injecting α-Syn preformed fibrils into mice with abundant Aβ plaques. Recent pathological studies in vitro showed that AD-related pathologies could exacerbates α-Syn seeding activity and neurotoxicity ( 43 , 44 ), suggesting an interaction between α-Syn pathology and AD-type pathologies in PD-CI.…”

Section: Pathological Characteristics Of Pd-cimentioning

confidence: 99%

Porphyromonas gingivalis: A key role in Parkinson's disease with cognitive impairment?

Ren

et al. 2022

Front. Neurol.

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Cognitive impairment (CI) is a common complication of Parkinson's disease (PD). The major features of Parkinson's disease with cognitive impairment (PD-CI) include convergence of α-Synuclein (α-Syn) and Alzheimer's disease (AD)-like pathologies, neuroinflammation, and dysbiosis of gut microbiota. Porphyromonas gingivalis (P. gingivalis) is an important pathogen in periodontitis. Recent research has suggested a role of P. gingivalis and its virulence factor in the pathogenesis of PD and AD, in particular concerning neuroinflammation and deposition of α-Synuclein (α-Syn) and amyloid-β (Aβ). Furthermore, in animal models, oral P. gingivalis could cause neurodegeneration through regulating the gut-brain axis, suggesting an oral-gut-brain axis might exist. In this article, we discussed the pathological characteristics of PD-CI and the role of P. gingivalis in them.

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APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology

Cited by 33 publications

References 71 publications

LRP1 is a neuronal receptor for α-synuclein uptake and spread

LRP1 is a neuronal receptor for α-synuclein uptake and spread

Determining Whether Sex and Zygosity Modulates the Association between APOE4 and Psychosis in a Neuropathologically-Confirmed Alzheimer’s Disease Cohort

Porphyromonas gingivalis: A key role in Parkinson's disease with cognitive impairment?

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