APOE and APOE receptors in Lewy body dementia

Lewy body dementia, including dementia with Lewy bodies and Parkinson's disease dementia, is one of the most common causes of dementia after Alzheimer's disease. The APOE4 allele, the strongest genetic risk factor for late-onset Alzheimer's disease, also is the most replicated genetic risk factor for Lewy body dementia. Despite the evidence of an association between APOE4 and an increased risk and severity of Lewy body dementia, 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 Alzheimer's disease brains with Lewy copathology, as well as in Lewy body dementia brains with very minimal amyloid pathology, using a real-time quaking-induced conversion (RT-QuIC) assay.

Also, 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 induced pluripotent stem cell-derived neurons and transgenic mouse models with LRP1 gene knockout. The lab's research team is seeking to further understand the pathomechanisms of APOE and its receptors in Lewy body dementia with the goal to inhibit α-synuclein pathogenesis by targeting APOE, APOE receptors and related pathways.

Research highlights

• Jin Y, Li F, Li Z, Ikezu TC, O'Leary J, Selvaraj M, Zhu Y, Martens YA, Koga S, Santhakumar H, Li Y, Lu W, You Y, Lolo K, DeTure M, Beasley AI, Davis MD, McLean PJ, Ross OA, Kanekiyo T, Ikezu T, Caulfield T, Carr J, Wszolek ZK, Bu G, Dickson DW, Zhao N. Modeling Lewy body disease with SNCA triplication iPSC-derived cortical organoids and identifying therapeutic drugs. Science Advances 2024.
• 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.
• 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.
• 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.