APOE and APOE Receptors in Lewy Body Dementia
Lewy body dementia (LBD), including dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is one of the most common causes of dementia after AD. The APOE4 allele, the strongest genetic risk factor for late-onset AD, is also the most replicated genetic risk factor for LBD. Despite the evidence of an association between APOE4 and an increased risk and severity of LBD, the causal mechanism remains unclear.
Investigators in the lab have found that APOE4 worsens α-synuclein in animal models. In postmortem human brains, Dr. Zhao's team showed that α-synuclein seeding was exacerbated by APOE4 in AD brains with Lewy co-pathology, as well as in LBD brains with very minimal amyloid pathology, using a real-time quaking-induced conversion (RT-QuIC) assay.
Additionally, the lab has identified the low-density lipoprotein receptor-related protein 1 (LRP1), a well-characterized APOE receptor, as a key regulator of α-synuclein neuronal uptake. LRP1 also has been shown in the lab to act as an important mediator of α-synuclein spread in the brain using iPSC-derived neurons and transgenic mouse models with LRP1 gene knock-out. The lab's research team is seeking to further understand the pathomechanisms of APOE and its receptors in LBD with the goal to inhibit α-synuclein pathogenesis by targeting APOE, APOE receptors and related pathways.
Research highlights
- Chen K, Martens YA, Meneses A, Ryu DH, Lu W, Raulin AC, Li F, Zhao J, Chen Y, Jin Y, Linares C, Goodwin M, Li Y, Liu CC, Kanekiyo T, Holtzman DM, Golde TE, Bu G, Zhao N. LRP1 is a neuronal receptor for α-synuclein uptake and spread. Molecular Neurodegeneration. 2022; doi:10.1186/s13024-022-00560-w.
- Jin Y, Li F, Sonoustoun B, Kondru NC, Martens YA, Qiao W, Heckman MG, Ikezu TC, Li Z, Burgess JD, Amerna D, O'Leary J, DeTure MA, Zhao J, McLean PJ, Dickson DW, Ross OA, Bu G, Zhao N. APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology. Acta Neuropathologica. 2022; doi:10.1007/s00401-022-02421-8.
- Zhao N, Attrebi ON, Ren Y, Qiao W, Sonustun B, Martens YA, Meneses AD, Li F, Shue F, Zheng J, Van Ingelgom AJ, Davis MD, Kurti A, Knight JA, Linares C, Chen Y, Delenclos M, Liu CC, Fryer JD, Asmann YW, McLean PJ, Dickson DW, Ross OA, Bu G. APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid. Science Translational Medicine. 2020; doi:10.1126/scitranslmed.aay1809.